EP4747230A2 - Modulators of neurodegeneration - Google Patents

Modulators of neurodegeneration

Info

Publication number
EP4747230A2
EP4747230A2 EP24843910.1A EP24843910A EP4747230A2 EP 4747230 A2 EP4747230 A2 EP 4747230A2 EP 24843910 A EP24843910 A EP 24843910A EP 4747230 A2 EP4747230 A2 EP 4747230A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
independently selected
haloalkyl
haloalkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24843910.1A
Other languages
German (de)
French (fr)
Inventor
Changning Wang
Stephen Neil GOMPERTS
Ping Bai
Tim Bartels
Vikram Khurana
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCL Business Ltd
The Brigham and Women's Hospital Inc
General Hospital Corp
Original Assignee
UCL Business Ltd
The Brigham and Women's Hospital Inc
General Hospital Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UCL Business Ltd, The Brigham and Women's Hospital Inc, General Hospital Corp filed Critical UCL Business Ltd
Publication of EP4747230A2 publication Critical patent/EP4747230A2/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • TECHNICAL FIELD This invention relates to chemical compounds, and in particular to piperidine- 1-carboxylate compounds that are binders with high affinity to ⁇ -synuclein fibrils, as well as amyloid plaques and/or tau tangles in brain tissues (e.g., neurons, glial cells, as well as the extracellular space). These compounds are useful, e.g., for treating neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia.
  • PD Parkinson’s disease
  • MSA multiple system atrophy
  • Lewy body dementia Lewy body dementia
  • the compounds When labeled with a radioisotope, such as 11 C, 18 F, or 123/125 I, the compounds are also positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents useful, e.g., as diagnostic tools for diagnosis and/or monitoring treatment of the neurodegenerative disorders.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • brain imaging agents useful, e.g., as diagnostic tools for diagnosis and/or monitoring treatment of the neurodegenerative disorders.
  • PD Parkinson’s disease
  • a synucleinopathy that affects movement, affects more than 10 million people worldwide with an estimated total annual economic burden of more than $52 billion.
  • AD Alzheimer’s disease
  • Pick’s disease a rare tauopathy characterized by a range of progressive neurological symptoms, affects 1 in 250,000 individuals with an estimated annual cost of treatment per patient of about $100,000.
  • neurodegenerative diseases impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging population worldwide, neurodegenerative disorders pose an increasing threat to public health.
  • piperidine-1-carboxylate compounds bind with high affinity to ⁇ -synuclein protein.
  • the compounds are also relatively selective for ⁇ -synuclein fibrils as opposed to amyloid plaques or tau tangles located in the brain tissues of individuals affected with neurodegeneration.
  • the piperidine-1-carboxylate compounds are about 30 ⁇ to about 50 ⁇ more selective to ⁇ -synuclein fibrils as compared to ⁇ -amyloid plaques.
  • the piperidine-1-carboxylate compounds are capable to permeate the blood brain barrier, to selectively and substantially accumulate in brain tissues (as opposed to any other tissues within a subject) upon administration, and to rapidly clear from the subject’s plasma upon exerting the therapeutic effect.
  • the specific affinity of piperidine-1- carboxylate compounds within the present claims to protein aggregates involved in pathology of neurodegenerative disorders allows using these compounds as brain imaging agents upon labeling the compounds with an appropriate radioisotope.
  • the compounds can be detected in the brain using PET, while when labeled with 123 I or 125 I, the compounds can be detected in the brain using SPECT.
  • the radiolabeled compounds are a useful diagnostic tool allowing to diagnose neurodegenerative disorders, to support clinical development of potential therapeutics (e.g., to screen drug candidate compounds for potential therapeutics), and to monitor treatment of the neurodegenerative disorders by the existing drugs and therapies.
  • the present disclosure provides a compound of Formula (I): I), or a pharmaceutically a ein R 1 , L 1 , X 1 , X 2 , and R 3 are as described herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating a neurodegenerative disease or disorder as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a therapeutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula (II): (II), or a pharmaceutically a in R 1 , L 1 , X 1 , X 2 , and R 3 are as described herein for Form ula (I), and the compound comprises at least one radioisotope selected from 11 C, 18 F, 123 I, 125 I, and 131 I.
  • the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of imaging a brain of a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of diagnosing a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of monitoring treatment of a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
  • FIG.1A contains a bar graph showing binding affinity (K D ) of SY08 to biotinylated alpha-synuclein preformed fibrils.
  • FIG.1B contains a bar graph showing binding affinity (K a ) of SY08 to biotinylated alpha-synuclein preformed fibrils.
  • FIG.1C contains a line plot showing R eq values estimated from sensorgrams vs. analyte concentration to estimate the Equilibrium Dissociation Constant (KD) for tested compounds.
  • FIG.2 contains table showing off-target binding profiling of SY08.
  • FIG.3 contains line plots showing binding of radioligand 3 H-SIL26 to tau, ⁇ - amyloid, and ⁇ -synuclein proteins.
  • FIG.4 contains a line plot showing radioligand binding to tau, ⁇ -amyloid, and ⁇ -synuclein proteins in the presence of SY-08.
  • FIG.5 schematically shows the iPSC model utilized for the radiometric cell binding assay.
  • FIG.6 contains a line plot showing increased binding of compound SY08 in the ⁇ -synuclein-overexpressing piggyBac inclusion model (upper line, solid) versus the control (dotted line).
  • FIG.7A shows IHC against phospho-alpha synuclein (left) and C 11 -SY08 ARG image on human postmortem tissue (right) (LBD, Anterior Cingulate). Note that the black circle was a technical artifact.
  • FIG.7B shows 3 H-SY08 ARG images on human postmortem tissue subject to washes with non-radiolabeled SY08 (LBD, grey matter in frontal cortex).
  • FIG.7C contains line plots showing that SY08 has selective binding affinity in PD tissues as compared to compounds C05-05, ACI-12589, and BF-227 (F18-C05-05, F18-ACI-12589 and F18-BF-227 have been used for PET imaging in MSA patients).
  • FIG.8 contains images showing results of autoradiography study on human postmortem tissues for compound 11 C SY08.
  • FIG.10 shows that an AAV1/2 expression system was used to drive the overexpression of mutant A53T human ⁇ -synuclein (aSyn) in the SNpc of rats, which resulted in ⁇ 60% loss of ipsilateral dopaminergic neurons after 21 days. Injection of empty AAV1/2 into the contralateral SNpc provided a vector-matched, within-animal control.
  • FIG.12B shows that dopamine transporter concentration was measured by C 11 -Altropane PET imaging before and after PB94 treatment. The right striatum showed more severe dopamine loss at baseline.
  • FIG.13A shows PET-MRI imaging in non-human primate (macaque) brain and contains summed PET SUVR images (0-90 mins, normalized by whole brain uptake) superimposed with MEMPRAGE-MRI of macaque brains, following injection of [ 11 C]SY08 in a baseline study.
  • FIG.13B shows PET-MRI imaging in non-human primate (macaque) brain. Regional brain analysis revealed that SUV values are between 1-2 across brain regions in early time points.
  • FIG.13C shows PET-MRI imaging in non-human primate (macaque) brain. Plasma radioactivity analysis revealed that the radioactivity was rapidly cleared from blood ( ⁇ 30 mins).
  • the major radiometabolites of [ 11 C]SY08 are with high polar, indicating the limited uptake of radiometabolites in brain.
  • DETAILED DESCRIPTION In neuropathology, neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as ⁇ - synuclein fibrils, amyloid- ⁇ plaques, and tau tangles, as well as by marked neuroinflammation.
  • the present disclosure provides compounds that selectively bind to protein aggregates that are implicated in neuropathology and neurodegeneration.
  • the compounds contribute to amelioration of neuronal loss and are therefore advantageously useful in treating the underlying neurological disorder (e.g., PD, MSA, PAF, AD, HD, or Pick’s disease).
  • the underlying neurological disorder e.g., PD, MSA, PAF, AD, HD, or Pick’s disease.
  • Certain embodiments of the therapeutic compounds e.g., compounds of Formula I
  • exemplary embodiments of diseases treatable by these compounds e.g., synucleinopathies
  • diagnosis of neurodegenerative conditions in clinic has been a persistent challenge due to the limitation of present neuropsychological tests and neuroimaging. Imaging pathological protein aggregates in brain via PET or SPECT provides a useful way to both diagnose the neurodegeneration process and to evaluate pharmacological performance of a drug treatment.
  • the compound when a PET or a SPECT imageable radioisotope (such as 11 C, 18 F, 123 I, or 125 I) is included in the chemical structure of the compound, the compound is useful as a radiotracer (an imaging agent) for diagnosing or monitoring treatment of various neurodegenerative conditions.
  • a radiotracer an imaging agent
  • Certain embodiments of the radiotracer compounds e.g., compounds of Formula II
  • exemplary embodiments of imaging methods in which the radiotracer compounds of this disclosure are advantageously useful, are described herein.
  • the present application provides a compound of Formula (I): (I), or a pharmaceutically ac ein R 1 , L 1 , X 1 , X 2 , and R 3 are as described herein.
  • X 1 is selected from O, NH, and S
  • L 1 is selected from bond and C 1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy
  • R 1 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 1A
  • X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is O or S. In some embodiments, X 1 is NH. In some embodiments, L 1 is a bond. In some embodiments, L 1 is C1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO 2 , C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy. In some embodiments, L 1 is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, or C 1-3 haloalkoxy.
  • L 1 is C 1-3 alkylene, optionally substituted with halo, CN, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, L 1 is C 1-3 alkylene (e.g., unsubstituted alkylene). In some embodiments, L 1 is selected from methylene, ethylene, and propylene. In some embodiments, R 1 is selected from C 6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with one substituent independently selected from R 1A . In some embodiments, R 1 is C6-10 aryl, optionally substituted with R 1A .
  • R 1 is 5-14 membered heteroaryl, optionally substituted with R 1A .
  • R 1 is C6-10 aryl (e.g., phenyl or naphthyl) substituted with R 1A .
  • R 1 is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R 1A .
  • R 1 is phenyl substituted with R 1A (e.g., in ortho, meta, or para position).
  • R 1 is naphthyl substituted with R 1A (e.g., in 1-, 2-, 3-, 5-, 6- 7-, or 8- position).
  • the compound of Formula (I) has formula: , or a pharmaceutically
  • the compound of Formula (I) has formula: , or a pharmaceutically
  • R 1A is selected from halo, CN, C 1-3 alkoxy, and C 1- 3 haloalkoxy.
  • X 1 is O;
  • L 1 is selected from bond and C 1-3 alkylene;
  • R 1a is C1-3 alkyl.
  • the compound of Formula (I) has formula: , or a pharmaceutically ac In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically .
  • L 2 is a bond. In some embodiments, L 2 is C 1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
  • L 2 is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, L 2 is C1-3 alkylene (e.g., methylene, ethylene, or propylene).
  • R 4 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl. In some embodiments, R 4 is H. In some embodiments, R 4 is C1-3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R 4 is C 1-3 haloalkyl.
  • R 4 is C1-3 alkyl substituted with Cy 2 and optionally substituted with halo or CN.
  • R 4 is C1-3 alkyl substituted with Cy 2 .
  • Cy 2 is C 6-10 aryl, optionally substituted with a substituent selected from R Cy , halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1- 3 haloalkoxy. In some embodiments, Cy 2 is C 6-10 aryl, substituted with R Cy and optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy 2 is C6-10 aryl substituted with R Cy .
  • Cy 2 is 5-14 membered heteroaryl, optionally substituted with a substituent selected from R Cy , halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1- 3 haloalkoxy. In some embodiments, Cy 2 is 5-14 membered heteroaryl, substituted with R Cy and optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C 1-3 haloalkoxy. In some embodiments, Cy 2 is 5-14 membered heteroaryl substituted with R Cy .
  • R Cy is C6-10 aryl, optionally substituted with halo, CN, C1-3 alkoxy, or C 1-3 haloalkoxy.
  • R Cy is C 6-10 aryl, optionally substituted with halo or CN.
  • R 4 is C1-3 alkyl substituted with C 6-10 aryl-C 6-10 aryl, wherein each of said C 6-10 aryl groups is optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy.
  • L 2 is C1-3 alkylene;
  • L 2 is a bond
  • R 4 is C1-3 alkyl substituted with Cy 2
  • Cy 2 is selected from C 6-10 aryl-R Cy and 5-14 membered heteroaryl-R Cy
  • each R Cy is independently selected from C6-10 aryl and 5-14 membered heteroaryl.
  • R 3 is C6-10 aryl (phenyl or naphthyl) substituted with R 1B .
  • R 3 is phenyl substituted with R 1B (e.g., in ortho, meta, or para position). In some embodiments, R 3 is naphthyl substituted with R 1B . In some embodiments, R 3 is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R 1B . In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutical In some embodiments, X 3 is selected from N and CH. In some embodiments, X 3 is N. In some embodiments, X 3 is CH.
  • the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically accep a e sa e eo .
  • the compound of Formula (I) is selected from any one of the following formulae: or a pharmace In some embodiments, the compound of Formula (I) has formula: or a pharmace In some embodiments, the compound of Formula (I) has formula:
  • the compound of Formula (I) is selected from any one of the following compounds: O N O O N Br O N S O N F Radiotracer compounds
  • the compound of Formula (I) as described above comprises at least one radioisotope selected from 11 C, 18 F, 123 I, 125 I, and 131 I.
  • the present disclosure provides a compound of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein the groups R 1 , L 1 , X 1 , X 2 , and R 3 are as described herein for Formula (I), and at least one of R 1 , L 1 , X 1 , X 2 , and R 3 comprises a radioisotope selected from 11 C, 18 F, 123 I, 125 I, and 131 I.
  • the compound of Formula (II) comprises 11 C.
  • the compound of Formula (II) comprises 18 F.
  • the compound of Formula (II) comprises 123 I.
  • L 2 is selected from bond and C 1-3 alkylene;
  • R 1A is selected from 11 CH3O-, 18 FCH2CH2O- and 18 FCH2CH2CH2O-.
  • the compound of Formula (II) is selected from any one of the following compounds: or a ph of.
  • Pharmaceutically acceptable salts In some embodiments, a salt of any one of the compounds of the present disclosure (e.g., compound of Formula I or Formula II) is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.
  • acids commonly employed to form pharmaceutically acceptable salts of the compounds include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phospho
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionat
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • bases commonly employed to form pharmaceutically acceptable salts of the compounds include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)
  • compositions, formulations, and routes of administration also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein.
  • the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein.
  • the carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as
  • compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients.
  • the contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.
  • Routes of administration and dosage forms The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra- arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,
  • compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in- oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches.
  • Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as ka
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • the pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration.
  • compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
  • the pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S.
  • Topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation.
  • the topical compositions can be in an emulsion form.
  • Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave- on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin- identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.
  • a compound of the present disclosure e.g., a compound of Formula (I) or Formula (II) is present in an effective amount.
  • the compound of Formula (I) may be present in a therapeutically effective amount.
  • the compound of Formula (II) may be present in an amount that is effective for imaging organ and/or tissues of a subject, such as for brain imaging as described herein.
  • Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other compounds, e.g., therapeutic treatments, other imaging agents, metabolism inhibitors, etc., and the judgment of the treating physician.
  • an effective amount of the compound can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about
  • an effective amount of a compound of Formula (I) or Formula (II) is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.
  • the foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month) as determined by a treating physician or a diagnostician (e.g., a practitioner responsible for administering an imaging agent).
  • a diagnostician e.g., a practitioner responsible for administering an imaging agent.
  • kits useful for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of the present disclosure, or an amount effective for imaging a brain of a subject of a compound of Formula (II) of the present disclosure.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the kit may optionally include an additional therapeutic agent as described herein.
  • the present disclosure provides a method of modulating ⁇ -synuclein, ⁇ -amyloid, and/or tau protein in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • the modulating comprises binding, inhibiting, or activating, or any combination of the foregoing.
  • the contacting occurs in vitro, in vivo, or ex vivo.
  • the cell is a brain cell (e.g., a neuron or a glial cell).
  • the modulation is selective with respect to ⁇ -synuclein, as opposed to ⁇ -amyloid, and/or tau protein (e.g., the modulation is 10 ⁇ , 20 ⁇ , 50 ⁇ , 100 ⁇ , or 1000 ⁇ more selective with respect to ⁇ -synuclein).
  • the present disclosure provides a method of modulating ⁇ -synuclein, ⁇ -amyloid, and/or tau protein in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • the compounds of Formula (I) and related salts and compositions of the present disclosure are useful in treating neurodegenerative disease or disorder that affects the motor system.
  • insoluble fibrillary synuclein e.g., ⁇ -synuclein or ⁇ Syn
  • insoluble fibrillary synuclein e.g., ⁇ -synuclein or ⁇ Syn
  • synucleinopathy refers to a group of neurodegenerative disorders where aggregation of insoluble synuclein (e.g., ⁇ Syn) protein fibrils in various CNS and/or peripheral nervous system (PNS) cells is implicated in pathology.
  • insoluble synuclein e.g., ⁇ Syn
  • PNS peripheral nervous system
  • the present disclosure provides a method of treating a synucleinopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the synucleinopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • a subject e.g., a subject in need of treatment, such as a subject identified as diagnosed with the synucleinopathy
  • the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • synucleinopathies include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Alzheimer’s disease, Hallervorden- Spatz syndrome, and lysosomal storage diseases (e.g., Gaucher’s disease), among other neurodegenerative disorders where synuclein is involved, at least in part, in the disease pathology.
  • Parkinson’s disease PD
  • MSA multiple system atrophy
  • PAF pure autonomic failure
  • OPCA olivopontocerebellar atrophy
  • SND striatonigral degeneration
  • neuroaxonal dystrophy Shy-Drager syndrome
  • Alzheimer’s disease Hallervorden- Spatz syndrome
  • lysosomal storage diseases e.g.,
  • amyloid peptide e.g., ⁇ -amyloid such as A ⁇ 40 peptide and/or A ⁇ 42 peptide
  • ⁇ -amyloid such as A ⁇ 40 peptide and/or A ⁇ 42 peptide
  • Numerous scientific publications provide credible evidence of association between neurodegeneration and amyloid peptide (e.g., ⁇ -amyloid such as A ⁇ 40 peptide and/or A ⁇ 42 peptide) misfolding and concomitant accumulation of amyloid peptide plaques in the brain. See, for example, Spires-Jones et al., Acta Neuropathologica, 134, 187–205, 2017; Selkoe D et al, J EMBO Mol. Med., 2016, 8, 6, 595-608; and Selkoe D et al, Science, 2002, 19; 297, 5580, 353-6, among many others.
  • amyloid peptide e.g., ⁇ -amyloid such as A ⁇ 40 peptide
  • ⁇ -amyloid is used as a diagnostic biomarker of Alzheimer’s disease (See, e.g., Nakamura et al., Nature, 2018, 554, 7691, 249-254, and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804, as well as its main target for therapeutics (See, e.g., Swanson C et al., Alzheimer’s Res. Ther., 2021, 13, 1, 80.
  • amyloidopathy or “ ⁇ -amyloidopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble amyloid plaques (e.g., ⁇ -amyloid plaques) in the brain is implicated in pathology.
  • the present disclosure provides a method of treating an amyloidopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the amyloidopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • amyloidopathies include premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders where formation of amyloid plaques is involved, at least in part, in the disease pathology.
  • AD Alzheimer’s disease
  • FAD familial AD
  • dementia associated with AD or FAD among other neurodegenerative disorders where formation of amyloid plaques is involved, at least in part, in the disease pathology.
  • Numerous scientific publications provide credible evidence of association between neurodegeneration and misfolding of the tau protein and subsequent formation of neurofibrillary or gliofibrillary tangles in the brain (e.g., neurons, glial cells, and extracellular space).
  • tauopathy refers to a group of neurodegenerative disorders where tau-positive inclusions in the brain are implicated in pathology.
  • the present disclosure provides a method of treating a tauopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the tauopathy), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • a subject e.g., a subject in need of treatment, such as a subject identified as diagnosed with the tauopathy
  • the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • tauopathies include Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease, among other neurodegenerative disorders where misfolding of tau protein is involved, at least in part, in the disease pathology.
  • the present disclosure provides a method of treating a neurodegenerative disorder where any combination of synuclein, amyloid, and/or tau peptide or protein is implicated in the disease pathology.
  • the present disclosure provides a method of treating a neurodegenerative disorder (e.g., where inflammation is implicated in the disease pathology) in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the neurodegenerative disorder), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • a neurodegenerative disorder e.g., where inflammation is implicated in the disease pathology
  • a subject e.g., a subject in need of treatment, such as a subject identified as diagnosed with the neurodegenerative disorder
  • the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • the neurodegenerative disorder is selected from motor neuron disease (MND), Prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), and dementia associated with HD, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger’s disease, dementia, multiple sclerosis (“MS”), hippocampal sclerosis, Gaucher’s disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinal cerebellar ataxias, disturbances of consciousness disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injuries (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar ataxia
  • MND
  • the disorder treatable by a compound of this disclosure is selected from accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret’s syndrome, Charcot–Marie–Tooth disease, diabetic neuropathy, nerve paralysis, and Horner’s syndrome.
  • Combination treatments The compounds of the present disclosure can be used on combination with at least one medication or therapy useful, e.g., in treating or alleviating symptoms of a neurodegenerative disorder such as PD.
  • Suitable examples of such medications include levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, istradefylline, donepezil, rivastigmine, galantamine, memantine, midodrine, fludrocortisone, physostigmine, droxidopa, botulinum toxin, or a pharmaceutically acceptable salt thereof.
  • dopamine agonists e.g., ropinirole, pramipexole, rotigotine
  • amantadine trihexyphenidyl
  • benztropine selegiline
  • rasagiline tolcapone
  • the compound can also be used in combination with deep brain stimulation (DBS) neurosurgery.
  • DBS deep brain stimulation
  • the compound of the present disclosure may be administered to the patient simultaneously with the additional therapeutic agent (in the same dosage form or in different dosage forms) or consecutively (the additional therapeutic agent may be administered before or after administration of the compound of the present disclosure).
  • Methods of imaging In one general aspect, the present application relates to compounds of Formula (II) useful in imaging techniques, diagnosing and monitoring treatment of various diseases and conditions described herein. Such compounds are labeled in so far as each compound includes at least one radioisotope (e.g., C, F, or I radioisotope as described herein). Imaging techniques such as PET and SPECT have become an important clinical diagnostic and research modality, and also a valuable technology in drug discovery and development.
  • PET offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short- lived positron-emitting radionuclide.
  • PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the photons formed as a result of the annihilation of the emitted positrons.
  • SPECT is a nuclear imaging scan that needs a radioactive tracer. The tracer is what allows doctors to see how blood flows to tissues and organs.
  • the radioisotopes typically used in SPECT are iodine- 123, technetium-99m, xenon-133, thallium-201, and fluorine-18. These radioactive forms of natural elements pass through the body and can be detected by the appropriate scanner.
  • PET offers the possibility of visualizing and analyzing the target proteins and/or protein aggregates under physiological and pathophysiological conditions. PET has often been used to detect disease-related biochemical changes before the disease-associated anatomical changes can be found using standard medical imaging modalities.
  • the present disclosure provides a method of identifying and/or quantifying to ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles in the brain of a subject. This may be attained, for example, by imaging the brain (e.g., due to binding affinity of compounds of Formula (II) to the aforementioned proteins and protein aggregates). Imaging the brain may include imaging midbrain, brain stem, thalamus, striatum, cerebellum, and/or cortex.
  • a method of imaging the brain comprises (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 1 hour, 2 hours, 3 hours, or 5 hours), and (iii) imaging the brain with an imaging technique.
  • 18 F and/or 11 C within the compound of Formula (II) are positron emitting radioisotopes
  • the suitable imaging techniques include positron emission tomography (PET) and its modification.
  • the imaging technique may be selected from positron emission tomography (PET) imaging, positron emission tomography with computer tomography (PET/CT) imaging, and positron emission tomography with magnetic resonance (PET/MRI) imaging.
  • PET positron emission tomography
  • PET/CT computer tomography
  • PET/MRI positron emission tomography with magnetic resonance
  • 123/125/131 I within the compound of Formula (II) are gamma emitting radiotracers
  • the suitable imaging techniques include single-photon emission computed tomography (SPECT) and it’s various modifications.
  • the present disclosure provides a method of diagnosing (or an early detection) a neurodegenerative disorder (e.g., neurodegenerative disorder in which ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles are implicated, such as any of the neurodegenerative disorders described herein) in a subject, the method comprising imaging a brain of a subject according to any of the imaging methods described herein.
  • a neurodegenerative disorder e.g., neurodegenerative disorder in which ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles are implicated, such as any of the neurodegenerative disorders described herein
  • the method of diagnosing a subject includes (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours), and (iii) imaging the brain with an imaging technique.
  • a time sufficient to allow the compound to accumulate in the brain to be imaged e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours
  • the method includes observing a signal in step iii) (e.g., observing a signal in an image obtained in step iii) attributable to the radioisotope in the compound of Formula (II) is indicative of the neurodegenerative disease in the subject.
  • the method may also comprise comparing images obtained from subjects exhibiting the symptoms of the disease or condition with the images obtained from healthy subjects.
  • overabundance of ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles in the brain of the subject may be indicative of a neurodegenerative disease such as Parkinson’s disease, Alzheimer’s disease, Pick’s disease, dementia, or a related condition.
  • the radiotracers of Formula (II) within the present claims are useful to study the molecular mechanisms involved in neurodegenerative diseases.
  • the compounds can be used to study molecular mechanisms leading to ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles formation.
  • the compound of Formula (II) can be co-administered with a modulator of a molecular mechanism suspected to be involved in ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles formation, and the absence or presence of those protein aggregates may be detected using an imaging technique as discussed herein.
  • the present disclosure provides a method of supporting a clinical development of potential therapeutics, which either prevent or inhibit formation of ⁇ - synuclein fibrils, amyloid plaques, and/or tau tangles, or lead to dissolution/degradation of those protein aggregates.
  • Potential therapeutics which either prevent or inhibit formation of ⁇ - synuclein fibrils, amyloid plaques, and/or tau tangles, or lead to dissolution/degradation of those protein aggregates.
  • In vivo imaging of pathological protein aggregates can help answer many vital questions in the drug discovery and development process such as whether potential drugs reach their molecular targets, the relationship between therapeutic dose and the desired outcome, the correlation between therapeutic affect and plasma drug levels, and the duration of time the drug remains at its target, and similar information.
  • the present disclosure provides a method of screening for potential therapeutics, for example, by detecting competitive binding of a drug candidate and a compound of Formula (II) to ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles in the brain.
  • a compound of Formula (II) can be administered first and a first brain image can be obtained with a signal attributable to radioisotope in compound of Formula (II), followed by administering a test compound and obtaining a second brain image.
  • the absence of a signal attributable to radioisotope in compound of Formula (II) in the second brain image may be indicative of test compound’s greater affinity to ⁇ - synuclein fibrils, amyloid plaques, and/or tau tangles in the brain and its potential therapeutic potency to treat associated neurodegenerative disorders.
  • the present disclosure provides a method of monitoring treatment of neurodegenerative disease (e.g., neurodegenerative disease in pathology of which ⁇ -synuclein fibrils, amyloid plaques, and/or tau tangles are implicated, such as any of the diseases described herein) in a subject, the method comprising (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, (ii) waiting a time sufficient to allow the compound of Formula (II) to accumulate in a brain of the subject (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (iii) imaging the brain of the subject with an imaging technique; (iv) administering to the subject a therapeutic agent in an effective amount to treat the neurodegenerative disorder.
  • neurodegenerative disease e.g., neurodegenerative disease in pathology of which ⁇ -synuclein fibrils,
  • aducanumab, lecanemab, donepezil, rivastigmine, galantamine, memantine, suvorexant, or an experimental drug substance for treating AD, or DLB, respectively may be administered to a subject undergoing treatment of AD, or undergoing treatment of DLB, respectively.
  • levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, an ⁇ - synuclein or LRRK2 (dardarin) antisense oligonucleotide (e.g., ASO by Biogen or ION859 and ION464 by Ionis), or an experimental drug substance for treating PD, or DLB, respectively, may be administered to a subject undergoing treatment of PD, or DLB, respectively.
  • dopamine agonists e.g., ropinirole, pramipexole, rotigotine
  • amantadine e.g., trihexyphenidyl
  • benztropine e
  • levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, fludrocortisone, midodrine, physostigmine, droxidopa, or an experimental drug substance for treating MSA may be administered to a subject undergoing treatment of MSA.
  • dopamine agonists e.g., ropinirole, pramipexole, rotigotine
  • amantadine e.g., trihexyphenidyl
  • benztropine e.g., selegiline, rasagiline, tolcapone, entacapone, fludrocortisone, midodrine, phy
  • the method further includes step (v) after (iv), administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (vi) waiting a time sufficient to allow the compound of Formula (II) to accumulate in the brain of the subject (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (vii) imaging the brain of the subject with an imaging technique; and (viii) comparing the image of step (iii) and the image of step (vii).
  • observing a reduced signal attributable to the radioisotope in the compound of Formula (II) in step viii) is indicative of progression of treatment of the neurodegenerative disease.
  • Suitable examples of diseases the treatment of which can be monitored according to the methods of the present disclosure include any of the diseases described herein. Some particular examples include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF).
  • AD Alzheimer’s disease
  • FAD familial AD
  • FAD frontotemporal lobar degeneration
  • HD Huntington’s disease
  • ALS amyotrophic lateral sclerosis
  • CTE chronic traumatic encephalopathy
  • aging- related tau astrogliopathy Richardson syndrome
  • cerebellar ataxia globular glial tauopathy
  • argyrophilic grain disease motor neuron disease (MND)
  • Prion disease Prion disease.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described.
  • a pyridine ring or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized ⁇ (pi) electrons where n is an integer).
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6- membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.
  • the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo
  • substitution at a given atom is limited by valency.
  • certain features of the invention which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.
  • various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
  • the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.
  • C n-m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • Cn-m alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons.
  • alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2- diyl, propan-1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3- diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like.
  • the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.
  • Cn-m haloalkyl refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings).
  • Cn-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring- forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)).
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10).
  • the cycloalkyl is a C 3-10 monocyclic or bicyclic cyclocalkyl.
  • the cycloalkyl is a C3-7 monocyclic cyclocalkyl.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heteroaryl refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl is a five- membered or six-membereted heteroaryl ring.
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heterocycloalkyl refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S.
  • heterocycloalkyl monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups.
  • Heterocycloalkyl groups can also include spirocycles.
  • Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3- isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.).
  • the heterocycloalkyl group can be attached through a ring- forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.
  • Cn-m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert- butoxy), and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m haloalkoxy refers to a group of formula –O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCF 3 .
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • halo refers to F, Cl, Br, or I.
  • a halo is F, Cl, or Br.
  • amino refers to a group of formula –NH2.
  • C n-m alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N- (n-butyl)amino and N-(tert-butyl)amino), and the like.
  • di(Cn-m-alkyl)amino refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • any atom identified in the compounds herein that is not specifically designated as radioisotope is present at is natural isotopic abundance.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and/or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.
  • the term “radioisotope” refers to an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • 18 F refers to the radioisotope of fluorine having 9 protons and 9 neutrons.
  • F refers to the stable isotope of fluorine having 9 protons and 10 neutrons (i.e., the “ 19 F isotope”).
  • a compound of the present disclosure has an isotopic enrichment factor for each designated 18 F atom of at least 3500 (52.5% 18 F incorporation at each designated 18 F atom), at least 4000 (60% 18 F incorporation), at least 4500 (67.5% 18 F incorporation), at least 5000 (75% 18 F), at least 5500 (82.5% 18 F incorporation), at least 6000 (90% 18 F incorporation), at least 6333.3 (95% 18 F incorporation), at least 6466.7 (97% 18 F incorporation), at least 6600 (99% 18 F incorporation), or at least 6633.3 (99.5% 18 F incorporation).
  • “ 11 C” refers to the radioisotope of carbon having 6 protons and 5 neutrons.
  • C refers to the stable isotope of carbon having 6 protons and 6 neutrons (i.e., the “ 12 C isotope”).
  • a compound of the present disclosure has an isotopic enrichment factor for each designated 11 C atom of at least 3500 (52.5% 11 C incorporation at each designated 11 C atom), at least 4000 (60% 11 C incorporation), at least 4500 (67.5% 11 C incorporation), at least 5000 (75% 11 C), at least 5500 (82.5% 11 C incorporation), at least 6000 (90% 11 C incorporation), at least 6333.3 (95% 11 C incorporation), at least 6466.7 (97% 11 C incorporation), at least 6600 (99% 11 C incorporation), or at least 6633.3 (99.5% 11 C incorporation).
  • 123 I refers to the radioisotope of iodine having 53 protons and 70 neutrons.
  • 125 I refers to the radioisotope of iodine having 53 protons and 72 neutrons.
  • 131 I refers to the radioisotope of iodine having 53 protons and 78 neutrons.
  • I refers to any abundant, stable isotope or a combination of stable, non-radioactive isotopes of iodine (e.g., the “ 127 I isotope”).
  • a compound of the present disclosure has an isotopic enrichment factor for each designated 123/125/131 I atom of at least 3500 (52.5% incorporation at each designated 123/125/131 I atom), at least 4000 (60% incorporation), at least 4500 (67.5% incorporation), at least 5000 (75% incorporation), at least 5500 (82.5% incorporation), at least 6000 (90% incorporation), at least 6333.3 (95% incorporation), at least 6466.7 (97% incorporation), at least 6600 (99% incorporation), or at least 6633.3 (99.5% incorporation).
  • Materials and methods All commercially available reagents were used without further purification unless otherwise stated.
  • Example 1 synthesis of compound 7-(methoxy- 11 C)naphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate ([ 11 C]SY-08) Step 1 – preparation of 7-methoxynaphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate To a solution of compound 4-(4-fluorophenyl)piperidine (4.5 g, 25.1 mmol) and compound 7-methoxynaphthalen-2-ol (4.37 g, 25.1 mmol) in dioxane (45 mL) was added CDI (4.07 g, 25.1 mmol).
  • Step 1 preparation of 7-hydroxynaphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate fluorophenyl)piperidine-1-carboxylate (4.90 g, 12.9 mmol) in CH2Cl2 (150 mL) was added TMSI (20.6 g, 103 mmol, 14.0 mL). The mixture was stirred at 50 °C for 24 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3).
  • Step 3 reaction with radiolabled reagent oxygen, with 11 MeV protons (Siemens Eclipse cyclotron), and trapped on molecular sieves in a TRACERlab FX-MeI synthesizer (General Electric).
  • [ 11 C]CH4 was obtained by the reduction of [ 11 C]CO2 in the presence of Ni/hydrogen at 350 °C, which re-circulated through an oven containing I2 to produce [ 11 C]CH3I via a radical reaction.
  • the prepared [ 11 C]CH3I was trapped in anhydrous DMF (300 ⁇ L) containing 7-hydroxynaphthalen-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylate (1.0 mg) and K 2 CO 3 (1.0 mg).
  • the reaction vessel was heated at 80 °C and kept there for 3 min.
  • the radioactive mixture containing [ 11 C]SY-08 was quenched by addition of an HPLC mobile phase (0.7 mL) and then applied to a reverse phase semipreparative HPLC (Agilent Eclipse XDB 5 ⁇ C18, 250 ⁇ 9.4 mm, 5.0 mL/min, a gradient of 10-90 % CH 3 CN in H 2 O of 0.1% TFA).
  • a radioactive fraction having a retention time of 12 min was collected in a flask, and diluted in water (30 mL).
  • the final product was reformulated by loading onto a solid-phase exchange (SPE) C-18 cartridge (Waters WAT020515 Sep-Pak Plus Short C18), rinsing with water (45 mL), eluting with EtOH (0.3 mL), and diluting with saline (2.7 mL).
  • SPE solid-phase exchange
  • the chemical and radiochemical purity of the final product was tested by analytical HPLC (VARIAN Puruit XRs 5 C18, 150 ⁇ 4.6 mm), eluting with a gradient of 10-90 % CH3CN in H2O of 0.1% TFA, at a flow rate of 2 mL/min.
  • Example 2 synthesis of compound 7-methoxynaphthalen-2-yl 4-(4- 18 F- phenyl)piperidine-1-carboxylate ([ 18 F]SY-08) O O 18F [ 18 F]SY08 was synthesized at the Athinoula A. Martinos Center for Biomedical Imaging Radioligand Lab at MGH from the CNY07 precursor, tetrakis(pyridine)copper triflate, pyridine and radioactive 18 F-. SY08 precursor, tetrakis(pyridine)copper triflate and pyridine were dissolved in DMF. This solution was added to 18 F- in the presence of K2CO3 and KOTf.
  • the reaction mixture was concentrated under reduced pressure to remove dioxane.
  • the crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18150 ⁇ 40 mm ⁇ 10 ⁇ m; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%- 65% B over 15 min). title compound (30.0 mg, 86.8 ⁇ mol, 99.5% purity 4.87% yield) was obtained as yellow oil.
  • Step 2 preparation of N-([1,1'-biphenyl]-4-ylmethyl)-4-(4- fluorophenyl)piperidine-4-carboxamide ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (1.20 g, 2.46 mmol) in EtOAc (3.00 mL) was added HCl/EtOAc (4.00 M, 30.0 mL). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Title compound (0.80 g, 2.06 mmol, 83.8% yield) was obtained as white solid.
  • Step 3 preparation of 7-methoxynaphthalen-2-yl 4-(([1,1'-biphenyl]-4- ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate , fluorophenyl)piperidine-4-carboxamide (0.60 g, 1.54 mmol) in dioxane (5.00 mL) was added CDI (250 mg, 1.54 mmol) and 7-methoxynaphthalen-2-ol (269 mg, 1.54 mmol). The mixture was stirred at 100 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 4 preparation of SY101 ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (400 mg, 679 ⁇ mol) in DCM (3.00 mL) was added BBr3 (520 mg, 2.08 mmol, 0.20 mL). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by addition Na 2 CO 3 aq. at 0 °C to pH of about 7, and then diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL ⁇ 3).
  • Example 5 - radioligand binding assay for SY-08 Brain tissues were stored at ⁇ 80 °C until sectioning. Frozen tissue was trimmed with a razor blade and mounted on a cryostat chuck in a cryostat (Bright OTF 5000). Tissue sections were cut at a thickness of 20 ⁇ m. Sections were then thaw mounted onto Superfrost® slides (4 sections per slide). Slides were stored at 4 °C, together with silica desiccant, until required. After being removed from the 4 °C fridge, the slide box was allowed to warm to room temperature before opening.
  • Phosphor imager background determined in a region of the screen with no sections, was subtracted.
  • Non-specific binding determined in the presence of SY-08 10 ⁇ M was then subtracted from total binding to determine the specific binding.
  • Data was fitted using the non-linear curve fitting in Prism® (Graphpad Software Inc).
  • Phosphor images are shown in both grey scale and colour scale. The grey scale or colour scale range used for conversion from 16-bit phosphor imager files to 8-bit tiff files is shown next to each image.
  • the assay was carried out with reference compound SIL26 and radioligand 3 H-SIL26. Results are shown in Figures 3 and 4. The results indicate different binding sites on synuclein fibrils.
  • Example 6 Radioligand free binding test for SY-08 using biolayer interferometry (BLI)
  • the binding interaction between SY-08 and SIL-23 with the alpha-synuclein preformed fibrils was performed via BLI using the Octet Red384 instrument (Sartorius) using 1X PBS with 0.01% Brij-35 as the assay buffer.
  • the recombinant alpha-synuclein preformed fibrils (rPeptide, Cat# ASF-1001-1) were biotinylated using EZ-Link NHS-PEG4-Biotinylation Kit, and the excess label was removed with the Zeba spin desalting column following the manufacturer’s instructions (Thermo Fisher Scientific, Waltham, MA).
  • the biotinylated protein samples to be used as ‘load’ in the BLI experiments were purified in 1X PBS.
  • super streptavidin (SSA) sensors were used to detect the biophysical interaction between the small molecule ligand and the biotinylated proteins.
  • the super streptavidin sensors were soaked by dipping in 200 mL of assay buffer in a 96-well Greiner Bio-One Black flat bottom plate (#655209).
  • the assay was performed in a reaction volume of 80 mL in Greiner Bio-One 384 well black flat bottom PP plates (#781209, Greiner, Monroe, North Carolina) with an initial baseline step, followed by loading of 4 mM (4000 nM) biotinylated protein.
  • Req is plotted against the small molecule sample concentration to infer the Rmax.
  • KD is estimated as the small molecule concentration where 50% of Rmax is achieved.
  • SY-08 was evaluated in ⁇ -synuclein binding assay and compared to ⁇ - synuclein fibril binding radioligand SIL23: . The results are s data indicates SY08 binds strongly based on the estimated values of the equilibrium dissociation constant when compared with SIL-23.
  • the estimated association rate constant for SY-08 was at least 7-fold higher than that estimated for SIL-23.
  • the association rate constant (Ka) represents the number of complexes formed per second between the small molecule and the biotinylated protein in a 1 M solution.
  • Human iPSC models enable SY-08 to be tested not only in human neurons, but in a neuronal model system engineered with a piggyBac that is scalable to be generated at scale in a patient-specific manner, and in conjunction with ⁇ -syn overexpression to boost the signal to noise.
  • the failure of ⁇ -syn binders hitherto in the clinic may have been attributable to inadequate testing in the appropriate human CNS context prior to clinical use.
  • This model system seeks to address that gap.
  • Example 8 - SY08 autoradiography on human postmortem tissues A full characterization of a PET tracer is a lengthy and expensive procedure, and it is necessary to establish confidence via a number of assays that a tracer will provide useful data in the target species (generally human).
  • Autoradiography performed as an ex vivo binding technique or as ex vivo recording of in vivo tracer distribution are, in this respect, very important tools.
  • Autoradiography binding methods allow a range of frozen tissues to be sectioned and incubated with the PET tracer, and with due caution and controls with selective blockade of binding, quantitative values can be obtained with respect to tracer binding and its regional distribution.
  • Ex vivo autoradiography of selected organs or whole animals gives qualitative images of a tracer’s distribution with high resolution. This method is attractive to use as a complement to small animal imaging due to its high resolution and anatomical correlate.
  • brain slices were prepared from frozen brain at 20 ⁇ m thickness and stored at -20 °C until they were used for experiments.
  • the tissue sections were preincubated with Tris ⁇ HCl buffer (pH 7.4, 50 mM) solution for 20 min at ambient temperature, followed by incubation with radiotracer (5 mCi/L) for 30 min at ambient temperature. After incubation, tissue sections were washed with Tris ⁇ HCl buffer two times for 5 min and dipped in cold distilled water for 10 s. The tissue sections were dried with cold air, then placed on imaging plates for 120 min. Autoradiograms were obtained and ROIs were carefully drawn with the reference of naked-eye observation. Radioactivity was expressed as digital light units per square millimeter (DLU/mm 2 ).
  • DLU/mm 2 digital light units per square millimeter
  • FIGS 7A-8 provide the assay results. SY08 showed over 70-fold selectivity for binding to PD tissues as compared to AD tissues.
  • FIG 7C see Amyloid-Beta Radiotracer [ 18 F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue, Contrast Media Mol Imaging.2018; 2018: 9165458; Discovery of [ 18 F]ACI-12589, a Novel and Promising PET-Tracer for Alpha-Synuclein.
  • [ 11 C]SY08 shows radiochemical yield (RCY) of 12% ⁇ 16% (non-decay corrected to trapped [ 11 C]CH 3 I), high molar activity of 1.82 ⁇ 0.2 Ci/ ⁇ mol (end of bombardment, EOB), over 99% chemical and radiochemical purity, 0.3-6 nM affinity toward ⁇ -syn, over 70-fold binding affinity selectivity for ⁇ -syn over A ⁇ /tau (human tissues), binding potential over 10 (ratio of Bmax/Kd), off-target binding over 10 ⁇ M, early peak uptake in rat brain of %ID/cc over 0.5, early peak uptake (0-10 mins) in non-human primate (NHP) BB permeability of SUV of 1-2, and rapid plasma clearance of less than 30 min with limited radiometabolites in brain.
  • RCY radiochemical yield
  • HDAC11 inhibitor PB94 has chemical structure: .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The present disclosure provides, e.g., piperidine-1-carboxylate compounds and methods of using these compounds, e.g., for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. The present disclosure also provides piperidine-1-carboxylate compounds radiolabeled with a radioisotope, such as 11C, 18F, or 123/125I, and method of using the radiolabeled compounds for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents for diagnosis and/or monitoring treatment of the neurodegenerative disorders.

Description

Modulators of Neurodegeneration CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No. 63/527,506, filed on July 18, 2023. The entire contents of the foregoing are incorporated herein by reference. TECHNICAL FIELD This invention relates to chemical compounds, and in particular to piperidine- 1-carboxylate compounds that are binders with high affinity to α-synuclein fibrils, as well as amyloid plaques and/or tau tangles in brain tissues (e.g., neurons, glial cells, as well as the extracellular space). These compounds are useful, e.g., for treating neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia. When labeled with a radioisotope, such as 11C, 18F, or 123/125I, the compounds are also positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents useful, e.g., as diagnostic tools for diagnosis and/or monitoring treatment of the neurodegenerative disorders. BACKGROUND There are numerous deadly diseases affecting current human population. For example, neurodegenerative diseases affect a significant segment of population, especially the elderly. As one example, Parkinson’s disease (“PD”), a synucleinopathy that affects movement, affects more than 10 million people worldwide with an estimated total annual economic burden of more than $52 billion. As another example, Alzheimer’s disease (“AD”), a β-amyloidopathy that affects approximately 44 million people world-wide, is the sixth leading cause of death with an estimated socioeconomic burden of more than $200 billion. In yet another example, Pick’s disease, a rare tauopathy characterized by a range of progressive neurological symptoms, affects 1 in 250,000 individuals with an estimated annual cost of treatment per patient of about $100,000. In sum, neurodegenerative diseases impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging population worldwide, neurodegenerative disorders pose an increasing threat to public health. SUMMARY The present disclosure is based, at least in part, on a realization that piperidine-1-carboxylate compounds bind with high affinity to α-synuclein protein. What is more, the compounds are also relatively selective for α-synuclein fibrils as opposed to amyloid plaques or tau tangles located in the brain tissues of individuals affected with neurodegeneration. In one example, the piperidine-1-carboxylate compounds are about 30× to about 50× more selective to α-synuclein fibrils as compared to β-amyloid plaques. What is more, the piperidine-1-carboxylate compounds are capable to permeate the blood brain barrier, to selectively and substantially accumulate in brain tissues (as opposed to any other tissues within a subject) upon administration, and to rapidly clear from the subject’s plasma upon exerting the therapeutic effect. Advantageously, the specific affinity of piperidine-1- carboxylate compounds within the present claims to protein aggregates involved in pathology of neurodegenerative disorders allows using these compounds as brain imaging agents upon labeling the compounds with an appropriate radioisotope. When labeled with 11C or 18F, the compounds can be detected in the brain using PET, while when labeled with 123I or 125I, the compounds can be detected in the brain using SPECT. The radiolabeled compounds are a useful diagnostic tool allowing to diagnose neurodegenerative disorders, to support clinical development of potential therapeutics (e.g., to screen drug candidate compounds for potential therapeutics), and to monitor treatment of the neurodegenerative disorders by the existing drugs and therapies. In one general aspect, the present disclosure provides a compound of Formula (I): I), or a pharmaceutically a ein R1, L1, X1, X2, and R3 are as described herein. In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In yet another general aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a therapeutically acceptable salt thereof. In yet another general aspect, the present disclosure provides a compound of Formula (II): (II), or a pharmaceutically a in R1, L1, X1, X2, and R3 are as described herein for Form ula (I), and the compound comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I. In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In yet another general aspect, the present disclosure provides a method of imaging a brain of a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof. In yet another general aspect, the present disclosure provides a method of diagnosing a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof. In yet another general aspect, the present disclosure provides a method of monitoring treatment of a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG.1A contains a bar graph showing binding affinity (KD) of SY08 to biotinylated alpha-synuclein preformed fibrils. FIG.1B contains a bar graph showing binding affinity (Ka) of SY08 to biotinylated alpha-synuclein preformed fibrils. FIG.1C contains a line plot showing Req values estimated from sensorgrams vs. analyte concentration to estimate the Equilibrium Dissociation Constant (KD) for tested compounds. FIG.2 contains table showing off-target binding profiling of SY08. SY08 did not have significant binding at 10 µM for the tested targets. MAO-A and MAO-B human enzymatic assays were performed at Cerep/Eurofins. The binding assays for the rest of targets were performed by the NIMH Psychoactive Drug Screening Program (PDSP). FIG.3 contains line plots showing binding of radioligand 3H-SIL26 to tau, β- amyloid, and α-synuclein proteins. FIG.4 contains a line plot showing radioligand binding to tau, β-amyloid, and α-synuclein proteins in the presence of SY-08. FIG.5 schematically shows the iPSC model utilized for the radiometric cell binding assay. Briefly, an iPSC model was engineered (see PCT/US2022/050468) with a piggyBac that induced rapid neuronal transdifferentiation in conjunction with α-synuclein over-expression (upper) or simple endogenous levels of α-synuclein expression (lower). These cells were seeded with synthetic of brain-derived α- synuclein pre-formed fibrils (schematized at top). FIG.6 contains a line plot showing increased binding of compound SY08 in the α-synuclein-overexpressing piggyBac inclusion model (upper line, solid) versus the control (dotted line). FIG.7A shows IHC against phospho-alpha synuclein (left) and C11-SY08 ARG image on human postmortem tissue (right) (LBD, Anterior Cingulate). Note that the black circle was a technical artifact. FIG.7B shows 3H-SY08 ARG images on human postmortem tissue subject to washes with non-radiolabeled SY08 (LBD, grey matter in frontal cortex). FIG.7C contains line plots showing that SY08 has selective binding affinity in PD tissues as compared to compounds C05-05, ACI-12589, and BF-227 (F18-C05-05, F18-ACI-12589 and F18-BF-227 have been used for PET imaging in MSA patients). FIG.8 contains images showing results of autoradiography study on human postmortem tissues for compound 11C SY08. FIG.9 shows results of PET imaging in α-synuclein A53T transgenic mouse (9-month old, n = 3)) using C11-SY08. The results show higher brain uptake than WT control mice. FIG.10 shows that an AAV1/2 expression system was used to drive the overexpression of mutant A53T human α-synuclein (aSyn) in the SNpc of rats, which resulted in ~60% loss of ipsilateral dopaminergic neurons after 21 days. Injection of empty AAV1/2 into the contralateral SNpc provided a vector-matched, within-animal control. Characteristics of this model included ipsilateral loss of dopamine cells identified with tyrosine hydroxylase staining (top), robust ipsilateral phosphorylation of aSyn at serine 129, a pathological feature of PD-associated aSyn A53T toxicity (middle), and the formation of proteinase K-resistant aggregates of aSyn (bottom). FIG.11A shows that PET imaging with C11-Altropane in AAV-αSynA53T rats (n = 3) showed dopamine loss in the right striatum, which is consistent with loss of TH+ cells in the right substantia nigra and loss of right striatal dopamine concentration measured with HPLC. FIG.11B shows that PET imaging with C11-SY08 in AAV-A53T-αSyn rats (n = 3) showed specific binding in the right substantia nigra, where aSyn is deposited. FIG.12A shows that an HDAC11 inhibitor, PB94, was used for treatment in AAV-A53T-αSyn rats (i.p. daily treatment for 3 weeks, n = 2). The aSyn aggregates measured in vivo by C11-SY08 PET imaging were reduced by treatment. FIG.12B shows that dopamine transporter concentration was measured by C11-Altropane PET imaging before and after PB94 treatment. The right striatum showed more severe dopamine loss at baseline. PB94 increased DAT concentration in both right SN and right striatum (n = 2). FIG.13A shows PET-MRI imaging in non-human primate (macaque) brain and contains summed PET SUVR images (0-90 mins, normalized by whole brain uptake) superimposed with MEMPRAGE-MRI of macaque brains, following injection of [11C]SY08 in a baseline study. FIG.13B shows PET-MRI imaging in non-human primate (macaque) brain. Regional brain analysis revealed that SUV values are between 1-2 across brain regions in early time points. FIG.13C shows PET-MRI imaging in non-human primate (macaque) brain. Plasma radioactivity analysis revealed that the radioactivity was rapidly cleared from blood (<30 mins). The major radiometabolites of [11C]SY08 are with high polar, indicating the limited uptake of radiometabolites in brain. DETAILED DESCRIPTION In neuropathology, neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as α- synuclein fibrils, amyloid-β plaques, and tau tangles, as well as by marked neuroinflammation. Together, these pathologies lead to a reduction of brain volume and brain cell number, degeneration of neurons, dysfunction of microglia, and the development of various neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), Pick’s disease, and dementia, including dementia specifically associated with any of the aforementioned disorders. Without being bound by any theory, in one general aspect, the present disclosure provides compounds that selectively bind to protein aggregates that are implicated in neuropathology and neurodegeneration. As such, the compounds contribute to amelioration of neuronal loss and are therefore advantageously useful in treating the underlying neurological disorder (e.g., PD, MSA, PAF, AD, HD, or Pick’s disease). Certain embodiments of the therapeutic compounds (e.g., compounds of Formula I) and exemplary embodiments of diseases treatable by these compounds (e.g., synucleinopathies) are described herein. Also, currently, diagnosis of neurodegenerative conditions in clinic has been a persistent challenge due to the limitation of present neuropsychological tests and neuroimaging. Imaging pathological protein aggregates in brain via PET or SPECT provides a useful way to both diagnose the neurodegeneration process and to evaluate pharmacological performance of a drug treatment. Without being bound by any theory, in a general aspect, when a PET or a SPECT imageable radioisotope (such as 11C, 18F, 123I, or 125I) is included in the chemical structure of the compound, the compound is useful as a radiotracer (an imaging agent) for diagnosing or monitoring treatment of various neurodegenerative conditions. Certain embodiments of the radiotracer compounds (e.g., compounds of Formula II) and exemplary embodiments of imaging methods in which the radiotracer compounds of this disclosure are advantageously useful, are described herein. Therapeutic compounds In some embodiments, the present application provides a compound of Formula (I): (I), or a pharmaceutically ac ein R1, L1, X1, X2, and R3 are as described herein. In some embodiments: X1 is selected from O, NH, and S; L1 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; R1 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1A; each R1A is independently selected from Cy1, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; X2 is selected from CR2 and N; R2 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from OH, CN, NO2, C1-3 alkoxy, and C1-3 haloalkoxy; L2 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; each R3 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1B; each R1B is independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each R1a is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each R4 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy2 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is O or S. In some embodiments, X1 is NH. In some embodiments, L1 is a bond. In some embodiments, L1is C1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, L1is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, L1is C1-3 alkylene, optionally substituted with halo, CN, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, L1is C1-3 alkylene (e.g., unsubstituted alkylene). In some embodiments, L1 is selected from methylene, ethylene, and propylene. In some embodiments, R1 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with one substituent independently selected from R1A. In some embodiments, R1 is C6-10 aryl, optionally substituted with R1A. In some embodiments, R1 is 5-14 membered heteroaryl, optionally substituted with R1A. In some embodiments, R1 is C6-10 aryl (e.g., phenyl or naphthyl) substituted with R1A. In some embodiments, R1 is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R1A. In some embodiments, R1 is phenyl substituted with R1A (e.g., in ortho, meta, or para position). In some embodiments, R1 is naphthyl substituted with R1A (e.g., in 1-, 2-, 3-, 5-, 6- 7-, or 8- position). In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, R1A is selected from halo, OH, CN, NO2, C1-3 alkyl, C1- 3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R1A is selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)O(C1-3 alkyl), and C(=O)NH(C1-3 alkyl). In some embodiments, R1A is selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)O(C1-3 alkyl), and C(=O)NH(C1-3 alkyl). In some embodiments, R1A is selected from halo, CN, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2. In some embodiments, R1A is selected from halo, CN, C1-3 alkoxy, and C1- 3 haloalkoxy. In some embodiments, R1A is halo. In some embodiments, R1A is CN. In some embodiments, R1A is C1-3 alkoxy. In some embodiments, R1A is C1-3 haloalkoxy. In some embodiments, R1A is Cy1. In some embodiments, Cy1 is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1 is C6-10 aryl. In some embodiments, Cy1 is C3-10 cycloalkyl. In some embodiments, Cy1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1 is C3- 10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1 is C6-10 aryl, optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C(=O)NH2. In some embodiments, Cy1 is (or R1A is) C6-10 aryl substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C(=O)NH2. In some embodiments, Cy1 is (or R1A is) C6-10 aryl substituted with halo, CN, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy1 is (or R1A is) C6-10 aryl substituted with halo. In some embodiments, Cy1 is (or R1A is) C6-10 aryl substituted with halo or CN. In some embodiments: X1 is O; L1 is selected from bond and C1-3 alkylene; each R1A is independently selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2; and each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, X2 is CR2. In some embodiments, X2 is N. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically acc In some embodiments, R2 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with OH, CN, NO2, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, R2 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4). In some embodiments, R2 is H. In some embodiments, R2 is C1-3 alkyl. In some embodiments, R2 is C1-3 haloalkyl. In some embodiments, R2 is L2- C(=O)N(R1a)(R4). In some embodiments, R2 is selected from H and L2- C(=O)N(R1a)(R4). In some embodiments, R1a is selected from H and C1-3 alkyl. In some embodiments, R1a is H. In some embodiments, R1a is C1-3 alkyl. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically ac In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically . In some embodiments, L2 is a bond. In some embodiments, L2 is C1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, L2 is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, L2 is C1-3 alkylene (e.g., methylene, ethylene, or propylene). In some embodiments, R4 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R4 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R4 is H. In some embodiments, R4 is C1-3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R4 is C1-3 haloalkyl. In some embodiments, R4 is C1-3 alkyl optionally substituted with 1 or 2 substituents independently selected from Cy2, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R4 is C1-3 alkyl substituted with Cy2 and optionally substituted with a substituent selected from CN, NO2, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)NH(C1-3 alkyl), and C(=O)N(C1-3 alkyl)2. In some embodiments, R4 is C1-3 alkyl substituted with Cy2 and optionally substituted with halo or CN. In some embodiments, R4 is C1-3 alkyl substituted with Cy2 and C(=O)NH(C1-3 alkyl) and optionally substituted with halo or CN. In some embodiments, R4 is C1-3 alkyl substituted with Cy2. In some embodiments, R4 is C1-3 alkyl substituted with Cy2 and C(=O)NH(C1-3 alkyl). In some embodiments, Cy2 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with a substituent selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), and C(=O)N(C1-3 alkyl)2. In some embodiments, Cy2 is C6-10 aryl, optionally substituted with a substituent selected from RCy, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1- 3 haloalkoxy. In some embodiments, Cy2 is C6-10 aryl, substituted with RCy and optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy2 is C6-10 aryl substituted with RCy. In some embodiments, Cy2 is 5-14 membered heteroaryl, optionally substituted with a substituent selected from RCy, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1- 3 haloalkoxy. In some embodiments, Cy2 is 5-14 membered heteroaryl, substituted with RCy and optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy2 is 5-14 membered heteroaryl substituted with RCy. In some embodiments, RCy is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, or di(C1-3 alkyl)amino. In some embodiments, RCy is C6-10 aryl, optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, or C(=O)NH2. In some embodiments, RCy is C6-10 aryl, optionally substituted with halo, CN, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, RCy is C6-10 aryl, optionally substituted with halo or CN. In some embodiments, R4 is C1-3 alkyl substituted with C6-10 aryl-C6-10 aryl, wherein each of said C6-10 aryl groups is optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments: L2 is C1-3 alkylene; R4 is C1-3 alkyl substituted with Cy2 and C(=O)NH(C1-3 alkyl); Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl. In some embodiments: L2 is a bond; R4 is C1-3 alkyl substituted with Cy2; Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl. In some embodiments, each of said C6-10 aryl and 5-14 membered heteroaryl groups of Cy2 and RCy is optionally substituted with 1, 2, or 3 substituents (e.g., 1 or 2 substituents) independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3 alkyl). In some embodiments, R3 is C6-10 aryl (phenyl or naphthyl) substituted with R1B. In some embodiments, R3 is phenyl substituted with R1B (e.g., in ortho, meta, or para position). In some embodiments, R3 is naphthyl substituted with R1B. In some embodiments, R3 is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R1B. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutical In some embodiments, X3 is selected from N and CH. In some embodiments, X3 is N. In some embodiments, X3 is CH. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically accep a e sa e eo . In some embodiments, R1B is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)NH2, C(=O)OH, C(=O)O(C1-3 alkyl), and C(=O)NH(C1-3 alkyl). In some embodiments, R1B is halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C(=O)NH2. In some embodiments, R1B is halo, CN, C(=O)NH2, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, R1B is halo or CN. In some embodiments, R1B is halo. In some embodiments, R1B is CN. In some embodiments, R1B is C(=O)NH2. In some embodiments, R1B is C1-3 alkoxy or C1-3 haloalkoxy. In some embodiments, R1B is C1-3 haloalkoxy. In some embodiments, R1B is C1-3 alkoxy. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceuticall In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically In some embodiments, the compound of Formula (I) is selected from any one of the following formulae: or a pharmace . In some embodiments, X2 is selected from N, CH, and C-L2-C(=O)N(R1a)(R4). In some embodiments, the compound of Formula (I) is selected from any one of the following formulae: or a pharmace In some embodiments, the compound of Formula (I) has formula: or a pharmace In some embodiments, the compound of Formula (I) has formula:
or a pharmaceu In some embodiments, the compound of Formula (I) is selected from any one of the following compounds: O N O O N Br O N S O N F Radiotracer compounds In some embodiments, the compound of Formula (I) as described above comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I. Accordingly, in one general aspect, the present disclosure provides a compound of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein the groups R1, L1, X1, X2, and R3 are as described herein for Formula (I), and at least one of R1, L1, X1, X2, and R3 comprises a radioisotope selected from 11C, 18F, 123I, 125I, and 131I. In some embodiments, the compound of Formula (II) comprises 11C. In some embodiments, the compound of Formula (II) comprises 18F. In some embodiments, the compound of Formula (II) comprises 123I. In some embodiments, the compound of Formula (II) comprises 125I. In some embodiments, the compound of Formula (II) comprises 131I. In some embodiments, the compound of Formula (II) comprises a group selected from 18F, 123I, 125I, 131I, 11CN, 11C(=O)NH2, 11CH3-, 11CH3O-, 18FCH2CH2-, 18FCH2CH2O-, and 18FCH2CH2CH2O-. In some embodiments, R1B is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2. In some embodiments, R1B comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I. In some embodiments, R1B is selected from 18F, 123I, 125I, 131I, 11CN, 11C(=O)NH2, 11CH3-, 11CH3O-, 18FCH2CH2-, 18FCH2CH2O-, and 18FCH2CH2CH2O-. In some embodiments, the compound of Formula (II) has formula: , or a pharmaceuticall : X3 is selected from N and CH; and R1B is selected from 18F, 123I, and 125I. In some embodiments, R1B is selected from 11CN and 11C(=O)NH2. In some embodiments, R1B is selected from 18F, 11CN and 11C(=O)NH2. In some embodiments, R1B is selected from 123I and 125I. In some embodiments, R1B is selected from 11CH3- and 18FCH2CH2-. In some embodiments, R1B is selected from 11CH3O-, 18FCH2CH2O- and 18FCH2CH2CH2O-. In some embodiments, X2 is N. In some embodiments, X2 is CR2. In some embodiments, X2 is CH. In some embodiments: R2 is L2-C(=O)NHR4; L2 is selected from bond and C1-3 alkylene; R4 is C1-3 alkyl substituted with Cy2 and optionally substituted with C(=O)NH(C1-3 alkyl); Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, wherein each of said C6-10 aryl and 5-14 membered heteroaryl groups is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3 alkyl). In some embodiments: X1 is O; and L1 is selected from bond and C1-3 alkylene; each R1A is independently selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2; and each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, the compound of Formula (II) has formula: , or a pharmaceutic In some embodiments, the compound of Formula (II) has formula: R1A N O N X2 R3 S , or a pharmaceutic In some embodiments, the compound of Formula (II) has formula: , or a pharmaceutica In some embodiments, R1A is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2. In some embodiments, R1A comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I. In some embodiments, R1A is selected from 18F, 123I, 125I, 131I, 11CN, 11C(=O)NH2, 11CH3-, 11CH3O-, 18FCH2CH2-, 18FCH2CH2O-, and 18FCH2CH2CH2O-. In some embodiments, R1A is selected from 11CN and 11C(=O)NH2. In some embodiments, R1A is selected from 18F, 11CN, and 11C(=O)NH2. In some embodiments, R1A is selected from 123I and 125I. In some embodiments, R1A is selected from 11CH3- and 18FCH2CH2-. In some embodiments, R1A is selected from 11CH3O-, 18FCH2CH2O- and 18FCH2CH2CH2O-. In some embodiments, the compound of Formula (II) is selected from any one of the following compounds: or a ph of. Pharmaceutically acceptable salts In some embodiments, a salt of any one of the compounds of the present disclosure (e.g., compound of Formula I or Formula II) is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. Compositions, formulations, and routes of administration The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients. Routes of administration and dosage forms The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra- arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in- oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia. Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols. The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No.6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000. The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave- on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin- identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners. Dosages and regimens In the pharmaceutical compositions of the present application, a compound of the present disclosure (e.g., a compound of Formula (I) or Formula (II)) is present in an effective amount. For example, the compound of Formula (I) may be present in a therapeutically effective amount. In another example, the compound of Formula (II) may be present in an amount that is effective for imaging organ and/or tissues of a subject, such as for brain imaging as described herein. Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other compounds, e.g., therapeutic treatments, other imaging agents, metabolism inhibitors, etc., and the judgment of the treating physician. In some embodiments, an effective amount of the compound (e.g., Formula (I) or Formula (II)) can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; or from about 0.1 mg/kg to about 0.5 mg/kg). In some embodiments, an effective amount of a compound of Formula (I) or Formula (II) is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg. The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month) as determined by a treating physician or a diagnostician (e.g., a practitioner responsible for administering an imaging agent). Kits The present invention also includes kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of the present disclosure, or an amount effective for imaging a brain of a subject of a compound of Formula (II) of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein. Methods of treatment In some embodiments, the present disclosure provides a method of modulating α-synuclein, β-amyloid, and/or tau protein in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the modulating comprises binding, inhibiting, or activating, or any combination of the foregoing. In some embodiments, the contacting occurs in vitro, in vivo, or ex vivo. In some embodiments, the cell is a brain cell (e.g., a neuron or a glial cell). In some embodiments, the modulation is selective with respect to α-synuclein, as opposed to β-amyloid, and/or tau protein (e.g., the modulation is 10×, 20×, 50×, 100×, or 1000× more selective with respect to α-synuclein). In some embodiments, the present disclosure provides a method of modulating α-synuclein, β-amyloid, and/or tau protein in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the compounds of Formula (I) and related salts and compositions of the present disclosure are useful in treating neurodegenerative disease or disorder that affects the motor system. Numerous scientific publications provide credible evidence of association between multisystem neurodegeneration and progressive aggregation of insoluble fibrillary synuclein (e.g., α-synuclein or αSyn) in neurons and glia. See, for example, Galvin et al., Arch Neurol., 2001, 58, 2, 186-190 and Sekiya et al., Mol Neurodegeneration 16, 83, 2021, Wong Y et al, Nat. Med., 2017, 23 (2), 1-13; Lashuel H et al., Nat. Rev. Neurosci., 2013, 14, 1, 38-48, among others. As such, without being bound by any particular theory or speculation, as used herein, the term “synucleinopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble synuclein (e.g., αSyn) protein fibrils in various CNS and/or peripheral nervous system (PNS) cells is implicated in pathology. In some embodiments, the present disclosure provides a method of treating a synucleinopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the synucleinopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of synucleinopathies include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Alzheimer’s disease, Hallervorden- Spatz syndrome, and lysosomal storage diseases (e.g., Gaucher’s disease), among other neurodegenerative disorders where synuclein is involved, at least in part, in the disease pathology. Numerous scientific publications provide credible evidence of association between neurodegeneration and amyloid peptide (e.g., β-amyloid such as Aβ40 peptide and/or Aβ42 peptide) misfolding and concomitant accumulation of amyloid peptide plaques in the brain. See, for example, Spires-Jones et al., Acta Neuropathologica, 134, 187–205, 2017; Selkoe D et al, J EMBO Mol. Med., 2016, 8, 6, 595-608; and Selkoe D et al, Science, 2002, 19; 297, 5580, 353-6, among many others. In one example, β-amyloid is used as a diagnostic biomarker of Alzheimer’s disease (See, e.g., Nakamura et al., Nature, 2018, 554, 7691, 249-254, and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804, as well as its main target for therapeutics (See, e.g., Swanson C et al., Alzheimer’s Res. Ther., 2021, 13, 1, 80. As such, without being bound by any particular theory or speculation, as used herein, the term “amyloidopathy” or “β-amyloidopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain is implicated in pathology. In some embodiments, the present disclosure provides a method of treating an amyloidopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the amyloidopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of amyloidopathies include premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders where formation of amyloid plaques is involved, at least in part, in the disease pathology. Numerous scientific publications provide credible evidence of association between neurodegeneration and misfolding of the tau protein and subsequent formation of neurofibrillary or gliofibrillary tangles in the brain (e.g., neurons, glial cells, and extracellular space). See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb Clin Neurol, 2017, 145, 355-368; Guo J et al., Cell, 2013, 154, 1, 103-17; Giasson et al., Science, 2003, 300, 5619, 636-40; and Bassil F et al., Neuron, 2020, 105, 2, 260-275, among many others. As such, without being bound by any particular theory or speculation, as used herein, the term “tauopathy” refers to a group of neurodegenerative disorders where tau-positive inclusions in the brain are implicated in pathology. In some embodiments, the present disclosure provides a method of treating a tauopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the tauopathy), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of tauopathies include Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease, among other neurodegenerative disorders where misfolding of tau protein is involved, at least in part, in the disease pathology. In some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder where any combination of synuclein, amyloid, and/or tau peptide or protein is implicated in the disease pathology. See, e.g., Irwin D et al., Nat. Rev. Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodegener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol. Appl. Neurobiol., 2016, 42, 5, 436-50, among others. Without being bound by any particular theory or speculation, it is believed that misfolding and/or aggregation of synuclein, amyloid, and/or tau peptides or proteins causes, induces, increases, and/or enhances neuroinflammation, which process further contributes to the progression of neurodegeneration and related symptomology. See, e.g., Gate D et al, Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al, Elife, 2020, 9, e54083, among others. Accordingly, in some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder (e.g., where inflammation is implicated in the disease pathology) in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the neurodegenerative disorder), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the neurodegenerative disorder is selected from motor neuron disease (MND), Prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), and dementia associated with HD, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger’s disease, dementia, multiple sclerosis (“MS”), hippocampal sclerosis, Gaucher’s disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinal cerebellar ataxias, disturbances of consciousness disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injuries (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA). In some embodiments, the disorder treatable by a compound of this disclosure is selected from accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret’s syndrome, Charcot–Marie–Tooth disease, diabetic neuropathy, nerve paralysis, and Horner’s syndrome. Combination treatments The compounds of the present disclosure can be used on combination with at least one medication or therapy useful, e.g., in treating or alleviating symptoms of a neurodegenerative disorder such as PD. Suitable examples of such medications include levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, istradefylline, donepezil, rivastigmine, galantamine, memantine, midodrine, fludrocortisone, physostigmine, droxidopa, botulinum toxin, or a pharmaceutically acceptable salt thereof. The compound can also be used in combination with deep brain stimulation (DBS) neurosurgery. The compound of the present disclosure may be administered to the patient simultaneously with the additional therapeutic agent (in the same dosage form or in different dosage forms) or consecutively (the additional therapeutic agent may be administered before or after administration of the compound of the present disclosure). Methods of imaging In one general aspect, the present application relates to compounds of Formula (II) useful in imaging techniques, diagnosing and monitoring treatment of various diseases and conditions described herein. Such compounds are labeled in so far as each compound includes at least one radioisotope (e.g., C, F, or I radioisotope as described herein). Imaging techniques such as PET and SPECT have become an important clinical diagnostic and research modality, and also a valuable technology in drug discovery and development. PET offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short- lived positron-emitting radionuclide. Carbon-11 (radioactive half-life (t1/2) = 20.4 min) and fluorine-18 (t1/2 = 109.7 min) are the most commonly used radionuclides in PET imaging. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the photons formed as a result of the annihilation of the emitted positrons. SPECT is a nuclear imaging scan that needs a radioactive tracer. The tracer is what allows doctors to see how blood flows to tissues and organs. The radioisotopes typically used in SPECT are iodine- 123, technetium-99m, xenon-133, thallium-201, and fluorine-18. These radioactive forms of natural elements pass through the body and can be detected by the appropriate scanner. As a noninvasive medical and molecular imaging technique and a powerful tool in neurological research, PET offers the possibility of visualizing and analyzing the target proteins and/or protein aggregates under physiological and pathophysiological conditions. PET has often been used to detect disease-related biochemical changes before the disease-associated anatomical changes can be found using standard medical imaging modalities. In some embodiments, the present disclosure provides a method of identifying and/or quantifying to α-synuclein fibrils, amyloid plaques, and/or tau tangles in the brain of a subject. This may be attained, for example, by imaging the brain (e.g., due to binding affinity of compounds of Formula (II) to the aforementioned proteins and protein aggregates). Imaging the brain may include imaging midbrain, brain stem, thalamus, striatum, cerebellum, and/or cortex. A method of imaging the brain comprises (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 1 hour, 2 hours, 3 hours, or 5 hours), and (iii) imaging the brain with an imaging technique. In one example, 18F and/or 11C within the compound of Formula (II) are positron emitting radioisotopes, the suitable imaging techniques include positron emission tomography (PET) and its modification. As such, the imaging technique may be selected from positron emission tomography (PET) imaging, positron emission tomography with computer tomography (PET/CT) imaging, and positron emission tomography with magnetic resonance (PET/MRI) imaging. In another example, 123/125/131I within the compound of Formula (II) are gamma emitting radiotracers, the suitable imaging techniques include single-photon emission computed tomography (SPECT) and it’s various modifications. In some embodiments, the present disclosure provides a method of diagnosing (or an early detection) a neurodegenerative disorder (e.g., neurodegenerative disorder in which α-synuclein fibrils, amyloid plaques, and/or tau tangles are implicated, such as any of the neurodegenerative disorders described herein) in a subject, the method comprising imaging a brain of a subject according to any of the imaging methods described herein. In some embodiments, the method of diagnosing a subject includes (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours), and (iii) imaging the brain with an imaging technique. In some embodiments, the method includes observing a signal in step iii) (e.g., observing a signal in an image obtained in step iii) attributable to the radioisotope in the compound of Formula (II) is indicative of the neurodegenerative disease in the subject. The method may also comprise comparing images obtained from subjects exhibiting the symptoms of the disease or condition with the images obtained from healthy subjects. In one example, overabundance of α-synuclein fibrils, amyloid plaques, and/or tau tangles in the brain of the subject may be indicative of a neurodegenerative disease such as Parkinson’s disease, Alzheimer’s disease, Pick’s disease, dementia, or a related condition. In some embodiments, the radiotracers of Formula (II) within the present claims are useful to study the molecular mechanisms involved in neurodegenerative diseases. For example, the compounds can be used to study molecular mechanisms leading to α-synuclein fibrils, amyloid plaques, and/or tau tangles formation. For example, the compound of Formula (II) can be co-administered with a modulator of a molecular mechanism suspected to be involved in α-synuclein fibrils, amyloid plaques, and/or tau tangles formation, and the absence or presence of those protein aggregates may be detected using an imaging technique as discussed herein. In some embodiments, the present disclosure provides a method of supporting a clinical development of potential therapeutics, which either prevent or inhibit formation of α- synuclein fibrils, amyloid plaques, and/or tau tangles, or lead to dissolution/degradation of those protein aggregates. In vivo imaging of pathological protein aggregates can help answer many vital questions in the drug discovery and development process such as whether potential drugs reach their molecular targets, the relationship between therapeutic dose and the desired outcome, the correlation between therapeutic affect and plasma drug levels, and the duration of time the drug remains at its target, and similar information. In some embodiments, the present disclosure provides a method of screening for potential therapeutics, for example, by detecting competitive binding of a drug candidate and a compound of Formula (II) to α-synuclein fibrils, amyloid plaques, and/or tau tangles in the brain. In one example, a compound of Formula (II) can be administered first and a first brain image can be obtained with a signal attributable to radioisotope in compound of Formula (II), followed by administering a test compound and obtaining a second brain image. The absence of a signal attributable to radioisotope in compound of Formula (II) in the second brain image may be indicative of test compound’s greater affinity to α- synuclein fibrils, amyloid plaques, and/or tau tangles in the brain and its potential therapeutic potency to treat associated neurodegenerative disorders. In some embodiments, the present disclosure provides a method of monitoring treatment of neurodegenerative disease (e.g., neurodegenerative disease in pathology of which α-synuclein fibrils, amyloid plaques, and/or tau tangles are implicated, such as any of the diseases described herein) in a subject, the method comprising (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, (ii) waiting a time sufficient to allow the compound of Formula (II) to accumulate in a brain of the subject (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (iii) imaging the brain of the subject with an imaging technique; (iv) administering to the subject a therapeutic agent in an effective amount to treat the neurodegenerative disorder. In one example, aducanumab, lecanemab, donepezil, rivastigmine, galantamine, memantine, suvorexant, or an experimental drug substance for treating AD, or DLB, respectively, may be administered to a subject undergoing treatment of AD, or undergoing treatment of DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, an α- synuclein or LRRK2 (dardarin) antisense oligonucleotide (e.g., ASO by Biogen or ION859 and ION464 by Ionis), or an experimental drug substance for treating PD, or DLB, respectively, may be administered to a subject undergoing treatment of PD, or DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, fludrocortisone, midodrine, physostigmine, droxidopa, or an experimental drug substance for treating MSA may be administered to a subject undergoing treatment of MSA. In some embodiments, the method further includes step (v) after (iv), administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (vi) waiting a time sufficient to allow the compound of Formula (II) to accumulate in the brain of the subject (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (vii) imaging the brain of the subject with an imaging technique; and (viii) comparing the image of step (iii) and the image of step (vii). In one example, observing a reduced signal attributable to the radioisotope in the compound of Formula (II) in step viii) is indicative of progression of treatment of the neurodegenerative disease. Suitable examples of diseases the treatment of which can be monitored according to the methods of the present disclosure include any of the diseases described herein. Some particular examples include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF). Other suitable examples include Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging- related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease. Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized π (pi) electrons where n is an integer). The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-m alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2- diyl, propan-1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3- diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms. As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl. As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring- forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five- membered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3- isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring- forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position. As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert- butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m haloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term “Cn-m alkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N- (n-butyl)amino and N-(tert-butyl)amino), and the like. As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Any atom identified in the compounds herein that is not specifically designated as radioisotope is present at is natural isotopic abundance. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and/or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring. As used herein, the term “radioisotope” refers to an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). As used herein, the term “isotopic enrichment factor” refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. “18F” refers to the radioisotope of fluorine having 9 protons and 9 neutrons. “F” refers to the stable isotope of fluorine having 9 protons and 10 neutrons (i.e., the “19F isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designated 18F atom of at least 3500 (52.5% 18F incorporation at each designated 18F atom), at least 4000 (60% 18F incorporation), at least 4500 (67.5% 18F incorporation), at least 5000 (75% 18F), at least 5500 (82.5% 18F incorporation), at least 6000 (90% 18F incorporation), at least 6333.3 (95% 18F incorporation), at least 6466.7 (97% 18F incorporation), at least 6600 (99% 18F incorporation), or at least 6633.3 (99.5% 18F incorporation). “11C” refers to the radioisotope of carbon having 6 protons and 5 neutrons. “C” refers to the stable isotope of carbon having 6 protons and 6 neutrons (i.e., the “12C isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designated 11C atom of at least 3500 (52.5% 11C incorporation at each designated 11C atom), at least 4000 (60% 11C incorporation), at least 4500 (67.5% 11C incorporation), at least 5000 (75% 11C), at least 5500 (82.5% 11C incorporation), at least 6000 (90% 11C incorporation), at least 6333.3 (95% 11C incorporation), at least 6466.7 (97% 11C incorporation), at least 6600 (99% 11C incorporation), or at least 6633.3 (99.5% 11C incorporation). “123I” refers to the radioisotope of iodine having 53 protons and 70 neutrons. “125I” refers to the radioisotope of iodine having 53 protons and 72 neutrons. “131I” refers to the radioisotope of iodine having 53 protons and 78 neutrons. “I” refers to any abundant, stable isotope or a combination of stable, non-radioactive isotopes of iodine (e.g., the “127I isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designated 123/125/131I atom of at least 3500 (52.5% incorporation at each designated 123/125/131I atom), at least 4000 (60% incorporation), at least 4500 (67.5% incorporation), at least 5000 (75% incorporation), at least 5500 (82.5% incorporation), at least 6000 (90% incorporation), at least 6333.3 (95% incorporation), at least 6466.7 (97% incorporation), at least 6600 (99% incorporation), or at least 6633.3 (99.5% incorporation). EXAMPLES Materials and methods All commercially available reagents were used without further purification unless otherwise stated. Analytical thin layer chromatography (TLC) was performed using Silica Gel GF254 plates (Merck Millipore co, .ltd, 0.2 mm thick). Compounds were purified using CombiFlash Rf 150 (Teledyne ISCO co, .ltd).1H and 13C spectra were recorded on Bruker 500 MHz. Chemical shifts in 1H NMR spectra were reported in parts per million (ppm) on the δ scale from an internal standard of CDCl3 (7.26 ppm). Data were reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = Broad), coupling constant in hertz (Hz), and integration. Chemical shifts of 13C NMR spectra were reported in ppm from the central peak of CDCl3 (77.0 ppm) on the δ scale. MS data was recorded on Agilent Technologies 6310 quadrupole mass spectrometer. PET/CT/MR imaging was performed in anesthetized (isoflurane) animals to minimize discomfort. Highly trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for daily care. All mice were socially housed in cages appropriate for the physical and behavioral health of the individual animal and were given unlimited access to food and water, with additional nutritional supplements provided as prescribed by the attending veterinary staff. Example 1 – synthesis of compound 7-(methoxy-11C)naphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate ([11C]SY-08) Step 1 – preparation of 7-methoxynaphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate To a solution of compound 4-(4-fluorophenyl)piperidine (4.5 g, 25.1 mmol) and compound 7-methoxynaphthalen-2-ol (4.37 g, 25.1 mmol) in dioxane (45 mL) was added CDI (4.07 g, 25.1 mmol). The mixture was stirred at 100 °C for 12 hrs. TLC (Petroleum ether/ EtOAc = 10/ 1, Rf = 0.2) showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue, which was purified by column chromatography (SiO2, Petroleum ether/ EtOAc = 100/ 1 to 10/ 1), to give compound 7-methoxynaphthalen-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylate (5.50 g, 3.32 mmol, 22.9% purity, 13.2% yield) as a white solid. Step 1 – preparation of 7-hydroxynaphthalen-2-yl 4-(4- fluorophenyl)piperidine-1-carboxylate fluorophenyl)piperidine-1-carboxylate (4.90 g, 12.9 mmol) in CH2Cl2 (150 mL) was added TMSI (20.6 g, 103 mmol, 14.0 mL). The mixture was stirred at 50 °C for 24 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue, which was purified by prep-HPLC (column: Phenomenex luna C18250×50 mm × 10 µm; mobile phase: [water(TFA)- ACN]; gradient: 35%-75% B over ), to give title compound (200 mg, 547 μmol, 4.24% yield, 100% purity) as a white solid. LCMS: m/z = 366.0 (M+H)+, Rt = 1.879 min.1H NMR: (400 MHz, CD3OD) δ 7.76 (dd, J = 8.8, 4.4 Hz, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.31-7.38 (m, 2H), 7.05-7.19 (m, 5H), 4.32 (d, J = 11.2 Hz, 1H), 4.17 (d, J = 12.4 Hz, 1H), 3.14 (t, J = 12.4 Hz, 1H), 2.92-3.03 (m, 1H), 2.81-2.87 (m, 1H), 1.80- 1.83 (m, 2H), 1.59-1.74 (m, 2H). LCMS: m/z = 366.1 (M+H)+, Rt = 2.813 min. Step 3 – reaction with radiolabled reagent oxygen, with 11 MeV protons (Siemens Eclipse cyclotron), and trapped on molecular sieves in a TRACERlab FX-MeI synthesizer (General Electric). [11C]CH4 was obtained by the reduction of [11C]CO2 in the presence of Ni/hydrogen at 350 °C, which re-circulated through an oven containing I2 to produce [11C]CH3I via a radical reaction. The prepared [11C]CH3I was trapped in anhydrous DMF (300 μL) containing 7-hydroxynaphthalen-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylate (1.0 mg) and K2CO3 (1.0 mg). The reaction vessel was heated at 80 °C and kept there for 3 min. The radioactive mixture containing [11C]SY-08 was quenched by addition of an HPLC mobile phase (0.7 mL) and then applied to a reverse phase semipreparative HPLC (Agilent Eclipse XDB 5µ C18, 250 × 9.4 mm, 5.0 mL/min, a gradient of 10-90 % CH3CN in H2O of 0.1% TFA). A radioactive fraction having a retention time of 12 min was collected in a flask, and diluted in water (30 mL). The final product was reformulated by loading onto a solid-phase exchange (SPE) C-18 cartridge (Waters WAT020515 Sep-Pak Plus Short C18), rinsing with water (45 mL), eluting with EtOH (0.3 mL), and diluting with saline (2.7 mL). The chemical and radiochemical purity of the final product was tested by analytical HPLC (VARIAN Puruit XRs 5 C18, 150 × 4.6 mm), eluting with a gradient of 10-90 % CH3CN in H2O of 0.1% TFA, at a flow rate of 2 mL/min. Example 2 – synthesis of compound 7-methoxynaphthalen-2-yl 4-(4-18F- phenyl)piperidine-1-carboxylate ([18F]SY-08) O O 18F [18F]SY08 was synthesized at the Athinoula A. Martinos Center for Biomedical Imaging Radioligand Lab at MGH from the CNY07 precursor, tetrakis(pyridine)copper triflate, pyridine and radioactive 18F-. SY08 precursor, tetrakis(pyridine)copper triflate and pyridine were dissolved in DMF. This solution was added to 18F- in the presence of K2CO3 and KOTf. Following stirring for 20 minutes at 110 °C, the synthesized [18F]SY08 was purified using high performance liquid chromatography. The drug product was then reformulated into a vial containing 90% sterilized isotonic saline and 10% ethanol. The final product of [18F]SY08 underwent sterile filtration prior to administration. Example 3 – preparation of piperidine-1-carboxylate compounds Preparation of naphthalen-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylate (SY08-A) . Preparation of naphthalen-2-yl 4-(6-fluoropyridin-3-yl)piperidine-1- carboxylate (SY08-B) . Preparation of phenyl 4-(6-fluoropyridin-3-yl)piperidine-1-carboxylate . Preparation of 7-methoxynaphthalen-2-yl 4-(6-fluoropyridin-3-yl)piperidine- 1-carboxylate (SY08-C) Preparation of 2-bromobenzo[d]thiazol-5-yl 4-(4-fluorophenyl)piperidine-1- carboxylate (SY08-D) Preparation of (2-methoxypyrimidin-4-yl)methyl 4-(4-fluorophenyl)piperidine- 1-carboxylate (SY08-E) Route 1 A mixture of compound (2-methoxypyrimidin-4-yl)methanol (250 mg, 1.78 mmol), compound 4-(4-fluorophenyl)piperidine (319 mg, 1.78 mmol), CDI (289 mg, 1.78 mmol) in dioxane (2.50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18150×40 mm×10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%- 65% B over 15 min). title compound (30.0 mg, 86.8 μmol, 99.5% purity 4.87% yield) was obtained as yellow oil.1H NMR: 400 MHz, MeOD) δ 8.54 (d, J = 5.2 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.09 (d, J = 5.2 Hz, 1H), 7.05 - 6.98 (m, 2H), 5.17 (s, 2H), 4.46 - 4.22 (m, 2H), 4.01 (s, 3H), 3.16 - 2.87 (m, 2H), 2.79 (tt, J = 3.6, 12.2 Hz, 1H), 1.86 (br d, J = 13.0 Hz, 2H), 1.77 - 1.54 (m, 2H). Preparation of 4'-cyano-[1,1'-biphenyl]-4-yl 4-(6-fluoropyridin-3- yl)piperidine-1-carboxylate (SY08-F) Route 1 , , 1.02 mmol), compound 4-(4-fluorophenyl)piperidine (183 mg, 1.02 mmol), CDI (166 mg, 1.02 mmol) in dioxane (2.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18150×40 mm×10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%-82% B over 15 min). Title compound (30.0 mg, 74.9 μmol, 98.1% purity, 7.31% yield) was obtained as white solid.1H NMR: (400 MHz, CDCl3) δ 7.76 - 7.65 (m, 4H), 7.60 (d, J = 8.8 Hz, 2H), 7.25 (br s, 2H), 7.21 (dd, J = 5.4, 8.6 Hz, 2H), 7.03 (t, J = 8.8 Hz, 2H), 4.54 - 4.35 (m, 2H), 3.20 - 2.90 (m, 2H), 2.81 - 2.70 (m, 1H), 1.94 (br d, J = 13.4 Hz, 2H), 1.74 (dq, J = 4.6, 12.8 Hz, 2H. The following compounds were prepared using methods and procedures similar to those used to prepare SY08-A to F: 7-hydroxynaphthalen-2-yl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4- fluorophenyl)piperidine-1-carboxylate (SY101) Step 1 – preparation of tert-butyl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)- 4-(4-fluorophenyl)piperidine-1-carboxylate fluorophenyl)piperidine-4-carboxylic acid (0.90 g, 2.78 mmol) in DCM (7.00 mL) was added HATU (1.06 g, 2.78 mmol) DIEA (359 mg, 2.78 mmol, 484 μL) and compound [1,1'-biphenyl]-4-ylmethanamine (510 mg, 2.78 mmol). The mixture was stirred at 20 °C for 1.5 hrs. TLC (Ethyl acetate, starting material: Rf = 0.00, product: Rf = 0.49) showed the reaction was complete. The reaction mixture was extracted with H2O (10.0 mL). The combined organic layers were washed with DCM (35.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=25/1 to 2/1). Title compound (1.30 g, 2.66 mmol, 95.6% yield) was obtained as white solid.1H NMR: (400 MHz, CDCl3) δ 7.55 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.35 (dd, J = 5.4, 8.4 Hz, 3H), 7.15 - 7.03 (m, 4H), 4.41 (d, J = 5.6 Hz, 2H), 3.74 - 3.59 (m, 2H), 3.51 - 3.37 (m, 2H), 2.45 - 2.31 (m, 2H), 2.08 - 1.93 (m, 2H), 1.46 (s, 9H). Step 2 – preparation of N-([1,1'-biphenyl]-4-ylmethyl)-4-(4- fluorophenyl)piperidine-4-carboxamide ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (1.20 g, 2.46 mmol) in EtOAc (3.00 mL) was added HCl/EtOAc (4.00 M, 30.0 mL). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Title compound (0.80 g, 2.06 mmol, 83.8% yield) was obtained as white solid.1H NMR: (400 MHz, DMSO) δ 8.15 (t, J = 6.0 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.48 - 7.32 (m, 5H), 7.23 - 7.09 (m, 4H), 4.27 (d, J = 5.8 Hz, 2H), 2.84 - 2.74 (m, 2H), 2.71 - 2.64 (m, 2H), 2.47 - 2.40 (m, 2H), 1.80 - 1.64 (m, 2H). Step 3 – preparation of 7-methoxynaphthalen-2-yl 4-(([1,1'-biphenyl]-4- ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate , fluorophenyl)piperidine-4-carboxamide (0.60 g, 1.54 mmol) in dioxane (5.00 mL) was added CDI (250 mg, 1.54 mmol) and 7-methoxynaphthalen-2-ol (269 mg, 1.54 mmol). The mixture was stirred at 100 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Title compound (0.40 g, 679 μmol, 44.0% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.73 (dd, J = 9.0, 11.8 Hz, 2H), 7.58 - 7.48 (m, 4H), 7.47 - 7.32 (m, 6H), 7.17 - 7.05 (m, 7H), 5.57 - 5.49 (m, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.81 - 3.45 (m, 3H), 2.59 - 2.42 (m, 2H), 2.23 - 2.06 (m, 2H), 1.47 (s, 2H). Step 4 – preparation of SY101 ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (400 mg, 679 μmol) in DCM (3.00 mL) was added BBr3 (520 mg, 2.08 mmol, 0.20 mL). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by addition Na2CO3 aq. at 0 °C to pH of about 7, and then diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with brine 20.0 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150×25 mm × 5 µm; mobile phase: [water ( NH4HCO3)-ACN]; gradient:52.0%- 82.0% B over 9 min). Title compound (30.0 mg, 52.2 μmol, 98.9% purity 7.68% yield) was obtained as off-white solid.1H NMR: (400 MHz, DMSO) δ 9.78 (br s, 1H), 8.34 (br t, J = 5.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.50 - 7.39 (m, 5H), 7.38 - 7.32 (m, 1H), 7.27 - 7.13 (m, 4H), 7.11 - 6.99 (m, 3H), 4.32 (br d, J = 5.8 Hz, 2H), 4.11 - 3.82 (m, 2H), 3.28 - 3.09 (m, 2H), 2.60 (br d, J = 11.0 Hz, 2H), 2.03 - 1.85 (m, 2H). 7-methoxynaphthalen-2-yl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4- fluorophenyl)piperidine-1-carboxylate (SY102) 4’-cyano-[1,1’-biphenyl]-4-yl 4-(2-((1-([1,1’-biphenyl]-4-yl)-3- (methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1- carboxylate (cmpd 415) (2-methoxypyrimidin-4-yl)methyl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3- (methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1- carboxylate (cmpd 419) O O N O N F 7-methoxynaphthalen-2-yl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3- oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (cmpd 423) 2-bromobenzo[d]thiazol-6-yl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)- 3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (cmpd 427) N O Br S O N F 4-cyclopropylphenyl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3- oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (cmpd 431) Example 4 – radiolabeled piperidine-1-carboxylate compounds The following radiolabeled compounds were prepared using methods and procedures similar to those provided in examples 1 and 2.
Example 5 - radioligand binding assay for SY-08 Brain tissues were stored at ˗80 °C until sectioning. Frozen tissue was trimmed with a razor blade and mounted on a cryostat chuck in a cryostat (Bright OTF 5000). Tissue sections were cut at a thickness of 20 µm. Sections were then thaw mounted onto Superfrost® slides (4 sections per slide). Slides were stored at 4 °C, together with silica desiccant, until required. After being removed from the 4 °C fridge, the slide box was allowed to warm to room temperature before opening. Slides were initially prewashed with ice-cold buffer for between 15 to 110 minutes and then placed horizontally in a humidified box.1 ml of incubation buffer containing [3H]SY- 08 (10 nM) alone (totals) or in the presence of the competing drug was layered over the sections. The sections were then incubated for 60 minutes at room temperature. Non-specific binding was defined using unlabelled SY-08 (10 µM). At the end of the incubation period, the radioligand solution was rapidly aspirated off and the slides were washed in ice-cold buffer (2 × 5 or 2 × 10 minutes, GBL_0715; 2 × 10 minutes, GBL_0731). Slides were then dried under a stream of air. After drying, sections were placed over a tritium-sensitive phosphor screen (Cytiva) and exposed for 7 days. Screens were then scanned on a PerkinElmer Cyclone® phosphor imager. Following phosphor imaging, selected sections were scraped from the slides using a razor blade, digested in 0.1 M NaOH for 1 hour, neutralized, mixed with scintillation cocktail and then counted in a liquid scintillation counter to measure the CPM per section. Image files (16-bit tiff files) from the phosphor imager were analysed using ImageJ (NIH). Regions-of-interest (ROIs) were drawn over each section. Radiotracer binding in the ROIs was quantified as digital light units (DLU) and averaged over the sections. Phosphor imager background, determined in a region of the screen with no sections, was subtracted. Non-specific binding, determined in the presence of SY-08 10 µM was then subtracted from total binding to determine the specific binding. Data was fitted using the non-linear curve fitting in Prism® (Graphpad Software Inc). Phosphor images are shown in both grey scale and colour scale. The grey scale or colour scale range used for conversion from 16-bit phosphor imager files to 8-bit tiff files is shown next to each image. The assay was carried out with reference compound SIL26 and radioligand 3H-SIL26. Results are shown in Figures 3 and 4. The results indicate different binding sites on synuclein fibrils. Example 6 - Radioligand free binding test for SY-08 using biolayer interferometry (BLI) The binding interaction between SY-08 and SIL-23 with the alpha-synuclein preformed fibrils was performed via BLI using the Octet Red384 instrument (Sartorius) using 1X PBS with 0.01% Brij-35 as the assay buffer. The recombinant alpha-synuclein preformed fibrils (rPeptide, Cat# ASF-1001-1) were biotinylated using EZ-Link NHS-PEG4-Biotinylation Kit, and the excess label was removed with the Zeba spin desalting column following the manufacturer’s instructions (Thermo Fisher Scientific, Waltham, MA). The biotinylated protein samples to be used as ‘load’ in the BLI experiments were purified in 1X PBS. For BLI, super streptavidin (SSA) sensors were used to detect the biophysical interaction between the small molecule ligand and the biotinylated proteins. Before the BLI assay, the super streptavidin sensors were soaked by dipping in 200 mL of assay buffer in a 96-well Greiner Bio-One Black flat bottom plate (#655209). The assay was performed in a reaction volume of 80 mL in Greiner Bio-One 384 well black flat bottom PP plates (#781209, Greiner, Monroe, North Carolina) with an initial baseline step, followed by loading of 4 mM (4000 nM) biotinylated protein. The biotinylated load protein and the small molecule samples were arranged in a 384-well plate as per a plate map compatible with the 8-channel mode kinetic analysis, where the sensors move from low to high concentration of the small molecule ligand. Additional steps included a second baseline (120s), association (240s), and dissociation (240s) for the subsequent cycles. All the sensors were loaded with the biotinylated protein, and three sensors with appropriate concentration of DMSO (comparable to small-molecule samples) in the assay buffer were used as the reference. Data were analyzed using Data Acquisition HT 12.0 software following reference subtraction (an average of three sensors with DMSO in assay buffer) using the 1:1 binding model with a global fit for the replicates (n=5). Global fit assumes complete dissociation of the binding partner (signal will return to zero at an infinite time). The equilibrium dissociation constant (KD) was also estimated using data at equilibrium from each available small molecule ligand concentration using the steady- state analysis. The instrument manufacturer (Fortebio, article #137) recommended the steady-state option for analyzing interactions that are either low affinity or with very fast on and off rates affinity or with very fast on and off rates. For steady-state analysis, R equilibrium (Req) was fitted according to the 1:1 binding model with the equation Response= (Rmax×Conc.)/(KD + Conc.). When the “R equilibrium” option is selected, Fortebio’s software calculated affinity constants based on the Req values determined from the resultant curve fits. In the steady-state analysis, Req is plotted against the small molecule sample concentration to infer the Rmax. KD is estimated as the small molecule concentration where 50% of Rmax is achieved. As per the instrument manufacturer, if all the curves have reached equilibrium, these two sets of values correspond to “Response,” and Req values should match. Additional descriptions about BLI assay are available on the manufacturer (ForteBio) website. SY-08 was evaluated in α-synuclein binding assay and compared to α- synuclein fibril binding radioligand SIL23: . The results are s data indicates SY08 binds strongly based on the estimated values of the equilibrium dissociation constant when compared with SIL-23. Additionally, the estimated association rate constant for SY-08 was at least 7-fold higher than that estimated for SIL-23. The association rate constant (Ka) represents the number of complexes formed per second between the small molecule and the biotinylated protein in a 1 M solution. These data strongly support that SY08 is more potent tracer than SIL-23 for alpha synuclein imaging use. Example 7 – radiometric cell binding assay using SY-08 shows increased binding in inclusion model Figures 5 and 6 provide details of the assay and the results for compound SY08 in a human iPSC model. Ultimately, the goal will be to utilize SY-08 in a human neuronal context. Human iPSC models enable SY-08 to be tested not only in human neurons, but in a neuronal model system engineered with a piggyBac that is scalable to be generated at scale in a patient-specific manner, and in conjunction with α-syn overexpression to boost the signal to noise. The failure of α-syn binders hitherto in the clinic may have been attributable to inadequate testing in the appropriate human CNS context prior to clinical use. This model system seeks to address that gap. Example 8 - SY08 autoradiography on human postmortem tissues A full characterization of a PET tracer is a lengthy and expensive procedure, and it is necessary to establish confidence via a number of assays that a tracer will provide useful data in the target species (generally human). These assays should also serve as a background to choose or to reject a tracer at an early time point, conserving valuable resources and time. Autoradiography performed as an ex vivo binding technique or as ex vivo recording of in vivo tracer distribution are, in this respect, very important tools. Autoradiography binding methods allow a range of frozen tissues to be sectioned and incubated with the PET tracer, and with due caution and controls with selective blockade of binding, quantitative values can be obtained with respect to tracer binding and its regional distribution. Ex vivo autoradiography of selected organs or whole animals gives qualitative images of a tracer’s distribution with high resolution. This method is attractive to use as a complement to small animal imaging due to its high resolution and anatomical correlate. Briefly, brain slices were prepared from frozen brain at 20 µm thickness and stored at -20 °C until they were used for experiments. The tissue sections were preincubated with Tris·HCl buffer (pH 7.4, 50 mM) solution for 20 min at ambient temperature, followed by incubation with radiotracer (5 mCi/L) for 30 min at ambient temperature. After incubation, tissue sections were washed with Tris·HCl buffer two times for 5 min and dipped in cold distilled water for 10 s. The tissue sections were dried with cold air, then placed on imaging plates for 120 min. Autoradiograms were obtained and ROIs were carefully drawn with the reference of naked-eye observation. Radioactivity was expressed as digital light units per square millimeter (DLU/mm2). In this experiment, it was found that the significant higher binding in the region enriched with alpha synuclein aggregates, than healthy control tissues, suggesting the specific binding of our traces in vitro. Figures 7A-8 provide the assay results. SY08 showed over 70-fold selectivity for binding to PD tissues as compared to AD tissues. Referring to Figure 7C, see Amyloid-Beta Radiotracer [18F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue, Contrast Media Mol Imaging.2018; 2018: 9165458; Discovery of [18F]ACI-12589, a Novel and Promising PET-Tracer for Alpha-Synuclein. ALZHEIMER'S & DEMENTIA , V.18, S6, Supplement: Biomarkers – Part 2, December 2022, E064680; High-Contrast Imaging of α-Synuclein Pathologies in Living Patients with Multiple System Atrophy. Movement Disorders, V.37, 10, October 2022, 2159-2161. (BF-227 ). Example 9 – [11C]SY08 for PET imaging [11C]SY08 shows radiochemical yield (RCY) of 12%−16% (non-decay corrected to trapped [11C]CH3I), high molar activity of 1.82 ± 0.2 Ci/μmol (end of bombardment, EOB), over 99% chemical and radiochemical purity, 0.3-6 nM affinity toward α-syn, over 70-fold binding affinity selectivity for α-syn over Aβ/tau (human tissues), binding potential over 10 (ratio of Bmax/Kd), off-target binding over 10 µM, early peak uptake in rat brain of %ID/cc over 0.5, early peak uptake (0-10 mins) in non-human primate (NHP) BB permeability of SUV of 1-2, and rapid plasma clearance of less than 30 min with limited radiometabolites in brain. Results are shown in Figures 9-13. Referring to Figure 12, HDAC11 inhibitor PB94 has chemical structure: . OTHER EMBODIMENTS It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I): (I), or a pharmaceuticall herein: X1 is selected from O , NH, and S; L1 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; R1 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1A; each R1A is independently selected from Cy1, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; X2 is selected from CR2 and N; R2 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from OH, CN, NO2, C1-3 alkoxy, and C1-3 haloalkoxy; L2 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; each R3 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1B; each R1B is independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each R1a is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each R4 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1- 3 alkyl)amino; each Cy2 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1- 3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1- 3 alkyl)amino. 2. The compound of claim 1, wherein: X1 is O; L1 is selected from bond and C1-3 alkylene; each R1A is independently selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2; and each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1,
2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2.
3. The compound of claim 1, wherein R3 is C6-10 aryl substituted with R1B.
4. The compound of claim 1, wherein R3 is 5-14 membered heteroaryl substituted with R1B.
5. The compound of any one of claims 1-4, wherein R1B is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2.
6. The compound of claim 1, wherein the compound of Formula (I) has formula: , or a pharmaceut
7. The compound of claim 1, wherein the compound of Formula (I) has formula: , or a pharmaceutical
8. The compound of claim 1, wherein the compound of formula (I) has formula: , or a pharmaceuticall
9. The compound of any one of claims 1-5, wherein the compound of Formula (I) has formula: , or a pharmaceutically acc
10. The compound of claim 9, wherein the compound of Formula (I) has formula: , or a pharmaceutically p .
11. The compound of claim 9, wherein the compound of Formula (I) has formula: , or a pharmaceutically
12. The compound of any one of claims 1-10, wherein: L2 is C1-3 alkylene; R4 is C1-3 alkyl substituted with Cy2 and C(=O)NH(C1-3 alkyl); Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, wherein each of said C6-10 aryl and 5-14 membered heteroaryl groups is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3 alkyl).
13. The compound of any one of claims 1-10, wherein: L2 is a bond; R4 is C1-3 alkyl substituted with Cy2; Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, wherein each of said C6-10 aryl and 5-14 membered heteroaryl groups is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3 alkyl).
14. The compound of claim 1, wherein the compound is selected from any one of the following compounds:
F
15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method of treating a neurodegenerative disease or disorder selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a therapeutically acceptable salt thereof.
17. A compound of Formula (II): I), or a pharmaceutical herein: the compound comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I; X1 is selected from O, NH, and S; L1 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; R1 is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1A; each R1A is independently selected from Cy1, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; X2 is selected from CR2 and N; R2 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from OH, CN, NO2, C1-3 alkoxy, and C1-3 haloalkoxy; L2 is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; each R3 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1B; each R1B is independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each R1a is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each R4 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1- 3 alkyl)amino; each Cy2 is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1- 3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1- 3 alkyl)amino.
18. The compound of claim 17, wherein R3 is C6-10 aryl substituted with R1B.
19. The compound of claim 17, wherein R3 is 5-14 membered heteroaryl substituted with R1B.
20. The compound of any one of claims 17-19, wherein R1B is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2.
21. The compound of claim 20, wherein R1B comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I.
22. The compound of claim 21, wherein R1B is selected from 18F, 123I, 125I, 131I, 11CN, 11C(=O)NH2, 11CH3-, 11CH3O-, 18FCH2CH2-, 18FCH2CH2O-, and 18FCH2CH2CH2O-.
23. The compound of claim 22, wherein the compound of Formula (II) has formula: , or a pharmace erein: X3 is selected from N and CH; and R1B is selected from 18F, 123I, and 125I.
24. The compound of any one of claims 17-23, wherein X2 is N.
25. The compound of any one of claims 17-23, wherein X2 is CR2.
26. The compound of claim 25, wherein X2 is CH.
27. The compound of claim 25, wherein: R2 is L2-C(=O)NHR4; L2 is selected from bond and C1-3 alkylene; R4 is C1-3 alkyl substituted with Cy2 and optionally substituted with C(=O)NH(C1-3 alkyl); Cy2 is selected from C6-10 aryl-RCy and 5-14 membered heteroaryl-RCy; and each RCy is independently selected from C6-10 aryl and 5-14 membered heteroaryl, wherein each of said C6-10 aryl and 5-14 membered heteroaryl groups is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3 alkyl).
28. The compound of any one of claims 17-27, wherein: X1 is O; and L1 is selected from bond and C1-3 alkylene; each R1A is independently selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2; and each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2.
29. The compound of claim 28, wherein R1A is selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2.
30. The compound of claim 29, wherein R1A comprises at least one radioisotope selected from 11C, 18F, 123I, 125I, and 131I.
31. The compound of claim 30, wherein R1A is selected from 18F, 123I, 125I, 131I, 11CN, 11C(=O)NH2, 11CH3-, 11CH3O-, 18FCH2CH2-, 18FCH2CH2O-, and 18FCH2CH2CH2O-.
32. The compound of claim 30 or 31, wherein the compound of Formula (II) is selected from any one of the following compounds: R3 or a pharmace .
33. The compound of claim 17, wherein the compound is selected from any one of the following compounds:
or a pharmaceu 34. A pharmaceutical composition comprising a compound of claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 35. A method of imaging a brain of a subject, the method comprising: i) administering to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged; and iii) imaging the brain with an imaging technique. 36. The method of claim 35, wherein the compound binds to α-synuclein fibrils, amyloid plaques, or tau tangles in the brain. 37. A method of diagnosing a neurodegenerative disease in a subject, the method comprising imaging a brain of a subject according to a method of claim 35, wherein observing a signal in step iii) attributable to the radioisotope in the compound of claim 17 is indicative of the neurodegenerative disease in the subject. 38. A method of monitoring treatment of a neurodegenerative disease in a subject, the method comprising: i) administering to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; ii) waiting a time sufficient to allow the compound to accumulate in a brain of the subject; iii) imaging the brain of the subject with an imaging technique; iv) administering to the subject a therapeutic agent in an effective amount to treat the neurodegenerative disease; v) after iv), administering to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; vi) waiting a time sufficient to allow the compound to accumulate in the brain of the subject; vii) imaging the brain of the subject with an imaging technique; and viii) comparing the image of step iii) and the image of step vii), wherein observing a reduced signal attributable to the radioisotope in the compound of claim 17 in step viii) is indicative of progression of treatment of the neurodegenerative disease. 39. The method of any one of claims 35-38, wherein the imaging technique is selected from positron emission tomography (PET) imaging, positron emission tomography with computer tomography (PET/CT) imaging, positron emission tomography with magnetic resonance (PET/MRI) imaging, and single-photon emission computerized tomography (SPECT) imaging. 40. The method of claim 37 or 38, wherein the neurodegenerative disease is selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a therapeutically acceptable salt thereof.
EP24843910.1A 2023-07-18 2024-07-17 Modulators of neurodegeneration Pending EP4747230A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363527506P 2023-07-18 2023-07-18
PCT/US2024/038385 WO2025019589A2 (en) 2023-07-18 2024-07-17 Modulators of neurodegeneration

Publications (1)

Publication Number Publication Date
EP4747230A2 true EP4747230A2 (en) 2026-05-27

Family

ID=94282584

Family Applications (1)

Application Number Title Priority Date Filing Date
EP24843910.1A Pending EP4747230A2 (en) 2023-07-18 2024-07-17 Modulators of neurodegeneration

Country Status (3)

Country Link
EP (1) EP4747230A2 (en)
CN (1) CN122249418A (en)
WO (1) WO2025019589A2 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2702950A1 (en) * 2007-10-16 2009-04-23 Northeastern University Methods and compounds for modulating cannabinoid activity
US9422286B2 (en) * 2014-01-27 2016-08-23 Washington University Metal-binding bifunctional compounds as diagnostic agents for Alzheimer's disease

Also Published As

Publication number Publication date
WO2025019589A3 (en) 2025-04-03
CN122249418A (en) 2026-06-19
WO2025019589A2 (en) 2025-01-23

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20260306

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR