Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/12—Organo silicon halides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
  • A61K51/1072—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• 18 F-SFB a radiolabeled prosthetic group that reacts with the ⁇ -amino group of surface- exposed lysine residues
• 18 F-SFB a radiolabeled prosthetic group that reacts with the ⁇ -amino group of surface- exposed lysine residues
• SiFAs Silicon fluoride acceptors
• PET positron emission tomography
• IEX 18 F- 19 F isotopic exchange reaction
• SiFA-based PET probes has been hampered by their high intrinsic lipophilicity, originating from bulky tert-butyl groups required for in vivo stabilization of the Si- 18 F bond.
• the problems associated with currently known SiFA- imaging probes in preclinical investigations are poor in vivo stability and unfavorable pharmacokinetic behavior.
• the present invention relates to a compound of Formula 1 :
• F is selected from the group consisting of 19 F and 18 F;
• a 1 is a monocyclic or bicyclic heteroaryl ring optionally substituted with
• R 1 and R 2 are each independently an alkyl group.
• a 1 is selected from the group consisting of indole, 7- azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine.
• R 1 and R 2 are tert-butyl groups.
• a 1 is selected from the group consisting of indole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine, and R 1 and R 2 are tert-butyl groups.
• the compound is selected from the group consisting of:
• the compound is selected from the group consisting of:
• the present invention also relates to a compound of Formula 2:
• F is selected from the group consisting of 19 F and 18 F;
• a 1 is a monocyclic or bicyclic heteroaiyl ring optionally substituted with
• a 2 is a linker
• a 3 is a moiety capable of chemical conjugation or bioconjugation
• a 4 is a moiety comprising a polar auxiliary that may optionally contain a charge
• R c , R d and R e are selected, at each independent occurrence, from the group consisting of H, and optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaiyl, heterocycloalkyl, aiylalkyl, heteroaiylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and any of R c , R d or R e can optionally be joined to form additional rings; and
• R 1 and R 2 are each independently an alkyl group.
• a 1 is selected from the group consisting of indole, 7- azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine.
• R 1 and R 2 are tert-butyl groups.
• a 1 is selected from the group consisting of indole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine, and R 1 and R 2 are tert-butyl groups.
• a 2 includes at least one of an unsubstituted alkyl, an unsubstituted polyethylene glycol (PEG), and a bisubstituted triazole.
• a 3 is selected from the group consisting of an N-hydroxysuccinimide (NHS) ester and maleimide.
• the compound of Formula 2 is a compound of
• F and A 1 is a monocyclic or bicyclic heteroaryl ring optionally substituted with
• a 2 is a linker
• a 3 is a moiety capable of chemical conjugation or bioconjugation
• a 4 is a moiety comprising a polar auxiliary that may optionally contain a charge
• a 5 is a moiety comprising a disease targeting molecule or biomolecule;
• R c , R d and R e are selected, at each independent occurrence, from the group consisting of H, and optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and any of R c , R d or R e can optionally be joined to form additional rings; and
• R 1 and R 2 are each independently an alkyl group.
• a 1 is selected from the group consisting of indole, 7- azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine.
• R 1 and R 2 are tert-butyl groups.
• a 1 is selected from the group consisting of indole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine, and R 1 and R 2 are tert-butyl groups.
• a 2 includes at least one of an unsubstituted alkyl, an unsubstituted polyethylene glycol (PEG), or a bisubstituted triazole.
• a 3 is selected from the group consisting of an NHS ester, a maleimide, an amide, and a maleimide-thiol adduct.
• the invention also relates to a method for imaging a biological target by
• the method includes the step of introducing into the target an imaging agent.
• the imaging agent includes a compound of Formula 1, and a ligand for the target.
• F in Formula 1 is 18 F.
• the ligand is a disease targeting molecule or biomolecule.
• the ligand is a peptide.
• the ligand is a protein.
• the ligand is an enzyme.
• the ligand is an antibody.
• the ligand is a small molecule.
• the imaging agent is obtained by site- selective chemical conjugation of the ligand with the compound.
• conjugation of the ligand occurs via a thiol group.
• conjugation of the compound occurs via a N-hydroxysuccinimide (NHS) ester, a maleimide, or a click chemistry adduct.
• NHS N-hydroxysuccinimide
• the present invention also relates to a kit for 18 F-labeling of a compound of the invention.
• the compound is a compound of Formula 1.
• the kit includes a compound of Formula 1 in which F is 19 F.
• the compound is a compound of Formula 2.
• the kit includes a compound of Formula 2 in which F is 19 F.
• the compound is a compound of Formula 3.
• the kit includes a compound of Formula 3 in which F is 19 F.
• the compound is a compound of Formula 4.
• the kit includes a compound of Formula 4 in which F is 19 F.
• the kit includes an 18 F isotopic exchange reagent.
• the kit includes an instruction manual for the use thereof. BRIEF DESCRIPTION OF THE DRAWINGS
• Figure 1 is a schematic illustrating an exemplary process for 18 F-labeling of an exemplary 1-methyl-indole heteroaromatic SiFA.
• Figure 2 is a schematic illustrating an exemplary one-step 18 F labeling process of 1-methyl-indole-SiFA on a microfluidic device.
• Figure 3 is a graph depicting the results of a kinetic study on RCCs over time in the IEX of an exemplary benzothiophene-SiFA and an exemplary 1-methyl- indole-SiFA with chip-produced [ 18 F]TBAF (tetra-n-butylammonium fluoride).
• Figure 4 is a graph depicting the results of a kinetic study on RCCs over time in the IEX of several different Het-SiFAs.
• Figure 5 depicts antibody fragment-based imaging of PSCA-expressing prostate cancer, specifically engineered PSCA-specific antibody fragments, namely Cys- diabodies (cDb), retaining high selective binding of the parental antibody yet exhibiting rapid blood clearance, making them suitable for labeling with short-lived radionuclides such as positron emitting Fluorine- 18.
• cDb Cys- diabodies
• the present invention relates to the unexpected discovery of novel heteroaromatic SiFAs useful for the 18 F-radiolabeling of biomolecules.
• This novel class of heteroaromatic SiFAs significantlyimproves many aspects of currently available phenyl SiFAs in terms of their preparation and pharmacokinetic properties.
• the synthesis of heteroaromatic SiFAs does not require the use of highly pyrophoric lithium or magnesium reagents, does not require prefunctionalization of the aryl, can potentially be scaled up to amounts that are of industrial interest, and uses cheaper and more environmentally friendly substrates which aligns with the current goals of sustainable chemistry.
• the aromatic heterocycles included are derivatives of indole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole and pyridine.
• the invention provides heteroaromatic SiFAs. In one embodiment, the invention provides 18 F-labeled compounds derived from SiFAs.
• the precursors for SiFAs are synthetically accessible by a methodology using potassium tert-butoxide as a catalyst for the silylation of C-H bonds in aromatic heterocycles, methodology described by Toutov et al., Nature, 2015, 518:80-84, which is incorporated by reference herein in its entirety.
• the invention provides methods for 18 F-radiolabeling of SiFAs by isotopic exchange.
• the isotopic exchange is performed on various platforms including a commercial radiosynthesizer (ELYXIS, Sofie
• the invention provides a kit for 18 F-radiolabeling of SiFAs by isotopic exchange.
• the invention provides methods for 18 F-based imaging methods, including, but not limited to, positron emission tomography (PET).
• PET positron emission tomography
• “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1%, and still more preferably ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
• the term "pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• the language "pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
• inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic.
• Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
• pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.
• alkaline earth metal salts e.g., calcium or magnesium
• alkali metal salts e.g., sodium-dependent or potassium
• ammonium salts e.g., ammonium salts.
• imaging agent means, unless otherwise stated, a molecule which can be detected by its emitted signal, such as positron emission, autofluorescence emission, or optical properties.
• the method of detection of the compounds may include, but are not necessarily limited to, nuclear scintigraphy, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging, magnetic resonance spectroscopy, computed tomography, or a combination thereof depending on the intended use and the imaging methodology available to the medical or research personnel.
• PET positron emission tomography
• SPECT single photon emission computed tomography
• magnetic resonance imaging magnetic resonance spectroscopy
• computed tomography or a combination thereof depending on the intended use and the imaging methodology available to the medical or research personnel.
• biomolecule refers to any molecule produced by a living organism and may be selected from the group consisting of proteins, peptides, polysaccharides, carbohydrates, lipids, as well as analogs and fragments thereof.
• biomolecules are proteins and peptides.
• bioconjugation and “conjugation,” unless otherwise stated, refers to the chemical derivatization of a macromolecule with another molecular entity.
• the molecular entity can be any molecule and can include a small molecule or another macromolecule.
• molecular entities include, but are not limited to, compounds of the invention, other macromolecules, polymers or resins, such as polyethylene glycol (PEG) or polystyrene, non-immunogenic high molecular weight compounds, fluorescent, chemiluminescent radioisotope and bioluminescent marker compounds, antibodies, biotin, diagnostic detector molecules, such as a maleimide derivatized fluorescein, coumarin, a metal chelator or any other modifying group.
• PEG polyethylene glycol
• polystyrene non-immunogenic high molecular weight compounds
• fluorescent, chemiluminescent radioisotope and bioluminescent marker compounds antibodies
• biotin diagnostic detector molecules, such as a maleimide derivatized fluorescein, coumarin, a metal chelator or any other modifying group.
• bioconjugation and conjugation are used interchangeably throughout the
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
• (Ci-C 6 )alkyl particularly ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.
• heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
• the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
• Up to two heteroatoms may be consecutive, such as, for example, -CH 2 - H-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3 .
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• the alkoxy group is (Ci-C 3 ) alkoxy, such as ethoxy and methoxy.
• halo or halogen alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• cycloalkyl refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
• the cycloalkyl group is saturated or partially unsaturated.
• the cycloalkyl group is fused with an aromatic ring.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
• Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
• Polycyclic cycloalkyls include adamantine and norbornane.
• cycloalkyl includes "unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
• heterocycloalkyl refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, Sand N.
• each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• the heterocycloalkyl group is fused with an aromatic ring.
• the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
• the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
• a heterocycle may be aromatic or non-aromatic in nature.
• the heterocycle is a heteroaryl.
• 3-membered heterocycloalkyl group includes, and is not limited to, aziridine.
• 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam.
• 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
• 6-membered heterocycloalkyl groups include, and are not limited to, piped dine, morpholine and piperazine.
• Other non-limiting examples of heterocycloalkyl groups are:
• non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3, 6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,
• aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized ⁇ (pi) electrons, where n is an integer.
• aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
• aryl groups include phenyl, anthracyl, and naphthyl.
• aryl-(Ci-C3)alkyl means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CifcCifc-phenyl. Preferred is aryl-CEh- and aryl-CH(CH3)-.
• substituted aryl-(Ci-C3)alkyl means an aryl-(Ci-C3)alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH2)-.
• heteroaryl- (Ci-C3)alkyl means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CEhCEh-pyridyl.
• the heteroaryl-(Ci-C3)alkyl is heteroaryl-(CH2)-.
• heteroaryl-(Ci-C3)alkyl means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted. In one embodiment, the substituted
• heteroaryl-(Ci-C3)alkyl is substituted heteroaryl-(CH2)-.
• heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
• a polycyclic heteroaryl may include one or more rings that are partially saturated. Exam les include the followin moieties:
• heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
• polycyclic heterocycles and heteroaryls examples include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly
• benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• substituted further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
• the substituents are
• the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.
• the term "optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
• the substituents are independently selected from the group consisting of oxo, halogen, -CN, - H 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , alkyl
• the substituents are independently selected from the group consisting of Ci-6 alkyl, -OH, Ci-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being preferred.
• ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
• an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the invention for its designated use.
• the instructional material of the kit of the invention may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.
• the present invention relates to the unexpected discovery of novel heteroaromatic SiFAs useful for the 18 F-radiolabeling of biomolecules.
• This novel class of heteroaromatic SiFAs exclusively improves many aspects of currently available phenyl SiFAs in terms of their preparation and pharmacokinetic properties.
• the huge variety of available heteroaromatic compounds that can be transformed into SiFAs enables the development of SiFAs with different electronic structures, polarities and free sites for derivatization, advantages which currently available phenyl SiFAs do not have.
• Table 1 highlights some of the unexpected improvements of exemplary compounds over a currently available SiFA:
• the compounds of the present invention may be synthesized using techniques well-known in the art of organic synthesis.
• the starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.
• the invention provides a compound of Formula 1 : A 1 ⁇ Si /
• F is selected from the group consisting of 19 F and 18 F;
• a 1 is a monocyclic or bicyclic heteroaryl ring optionally substituted with
• R c , R d and R e are selected, at each independent occurrence, from the group consisting of H, and optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and any of R c , R d or R e can optionally be joined to form additional rings; and
• R 1 and R 2 are each independently an alkyl group.
• the invention rovides a compound of Formula 2:
• F is selected from the group consisting of 19 F and 18 F;
• a 1 is a monocyclic or bicyclic heteroaryl ring optionally substituted with
• a 2 is a linker
• a 3 is a moiety capable of chemical conjugation or bioconjugation
• a 4 is a moiety comprising a polar auxiliary that may optionally contain a charge
• R c , R d and R e are selected, at each independent occurrence, from the group consisting of H, and optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and any of R c , R d or R e can optionally be joined to form additional rings; and
• R 1 and R 2 are each independently an alkyl group.
• the invention provides a compound of Formula 3 :
• F is selected from the group consisting of 19 F and 18 F; and m and n are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
• F is selected from the group consisting of 19 F and 18 F;
• a 1 is a monocyclic or bicyclic heteroaryl ring optionally substituted with
• a 2 is a linker
• a 3 is a moiety capable of chemical conjugation or bioconjugation
• a 4 is a moiety comprising a polar auxiliary that may optionally contain a charge
• a 5 is a moiety comprising a disease targeting molecule or biomolecule
• R c , R d and R e are selected, at each independent occurrence, from the group consisting of H, and optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and any of R c , R d or R e can optionally be joined to form additional rings; and
• R 1 and R 2 are each independently an alkyl group.
• the heteroaromatic ring A 1 is selected from the group consisting of indole, azaindole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine.
• R 1 and R 2 each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, and tert-butyl.
• R 1 and R 2 are tert-butyl groups.
• the heteroaromatic ring A 1 is selected from the group consisting of indole, 7-azaindole, benzothiophene, furan, pyrrole, pyrazole, imidazole, and pyridine, and R 1 and R 2 are tert-butyl groups.
• the linker A 2 includes an unsubstituted alkyl.
• the linker A 2 includes an unsubstituted polyethylene glycol (PEG).
• the linker A 2 includes a PEG4 linker.
• the linker A 2 includes a PEG6 linker.
• the linker A 2 includes a disubstituted triazole.
• a 3 is selected from the group consisting of an activated ester such as succinimide, an N- hydroxysuccinimide (NHS) ester, a maleimide, an amide, and a maleimide-thiol adduct.
• a PEG-spacer is added for additional polarity.
• a 4 is a carboxylic acid.
• a 5 is an engineered antibody fragment.
• a 5 is an anti-PSCA A2 cys-diabody.
• heteroaromatic SiFAs of the invention are highlighted in Tables 2 and 3 (the name indicates the corresponding heteroaromatic ring, and the substitution site indicates, without limitation, potential connectivity sites for a linker, and/or any other ancillary group):
• Compounds of Formulae 1, 2, 3, and 4 may be prepared by the general schemes described herein, using synthetic methods known by those skilled in the art. The following examples illustrate non-limiting embodiments of the invention.
• the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
• compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
• Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
• a mixture of one or more isomer is utilized as the therapeutic compound described herein.
• compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non- limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
• N-oxides if appropriate, crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity.
• Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
• the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol.
• the compounds described herein exist in unsolvated form.
• the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
• sites on, for example, the heteroaromatic or aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the heteroaromatic or aromatic ring structures may reduce, minimize or eliminate this metabolic pathway.
• the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
• reactive functional groups such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted
• Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
• each protective group is removable by a different means.
• Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
• protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
• reducing conditions such as, for example, hydrogenolysis
• oxidative conditions such as, for example, hydrogenolysis
• Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
• Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
• base labile groups such as, but not limited to, methyl, ethyl, and acetyl
• carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as
• Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
• an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base- labile acetate amine protecting groups.
• Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
• blocking/protecting groups may be selected from:
• the invention provides a method of synthesis of heteroaromatic Silicon-Fluoride Acceptors (SiFAs).
• SiFAs Silicon-Fluoride Acceptors
• the precursors for SiFAs are synthetically accessible by a methodology using potassium tert-butoxide as a catalyst for the silylation of C-H bonds in aromatic heterocycles, methodology described by Toutov et al., Nature, 2015, 518:80-84, which is incorporated herein in its entirety.
• Scheme 1 depicts an exemplary method for the synthesis of SiFAs.
• a heteroaromatic compound can be first treated with a catalytic amount of potassium tert-butoxide, and then reacted with di-tert-butyl silane, to afford an intermediate heteroarylsilane.
• the intermediate is thereafter reacted with potassium fluoride in the presence of a crown ether, to afford a 19 F-SiFA compound of the current invention.
• Compounds described herein include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, U C, 13 C, 14 C, 36 C1, 18 F, 123 I, 125 I, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, and 35 S.
• isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
• substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
• substitution with positron emitting isotopes such as U C, 18 F, 15 0 and 13 N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
• the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
• the invention provides methods for 18 F-radiolabeling of SiFAs by isotopic exchange.
• the novel class of heteroaromatic SiFAs described herein can be labeled with the PET isotope 18 F on various platforms.
• the isotopic exchange is performed on various platforms including a commercial
• radiosynthesizer (ELYXIS, Sofie Biosciences), an in-house developed microfluidic Teflon ® -coated chip, and a manual procedure in a sealed glass vial.
• Scheme 2 depicts an exemplary method of performing the 19 F to 18 F isotopic exchange. Accordingly, a 19 F-SiFA compound of the current invention can be exchanged with an 18 F-fluoride, to afford an 18 F-compound of the current invention.
• Purification of the labeled compound can be performed using any method known in the art.
• purification of the final labeling product is achieved by a cartridge purification (CI 8 or alumina).
• the present invention encompasses various kits for 18 F-labeling of heteroaromatic SiFAs, the kit comprising a heteroaromatic SiFA, an 18 F-labeling reagent, and an instructional materials which describe use of the kit to perform the methods of the invention. These instructions simply embody the methods and examples provided herein. Although model kits are described below, the contents of other useful kits will be apparent to the skilled artisan in light of the present disclosure. Each of these kits is contemplated within the present invention. A kit is envisaged for each embodiment of the present invention.
• the heteroaromatic SiFA of the present kit essentially includes the elements disclosed elsewhere herein.
• the heteroaromatic SiFA can comprise a monocyclic or bicyclic heteroaryl ring optionally substituted, a linker, a moiety capable of chemical conjugation or bioconjugation, a moiety comprising a polar auxiliary that may optionally contain a charge, and a moiety comprising a disease targeting molecule or biomolecule.
• the 18 F-labeling reagent can comprise [ 18 F]F " from the cyclotron.
• kits of the present invention can further comprise additional reagents disclosed herein, such as plates and dishes used in the methods of the present invention, buffers, solutions and the like, as well as an applicator or other implements for performing the methods of the present invention.
• the kits of the present invention further comprise an instructional material.
• the kit comprises micropipettes, vials, a Teflon ® -coated glass chip, a heater, and an alumina or other suitable purification cartridge.
• reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
• Example 1 Manual 18 F labeling of a SiFA in a sealed vial without adding a phase transfer catalyst or preceding 18 F activation
• the exemplary compound 1-methyl-indole-SiFA was labeled in a simple and fast radiosynthesis using wet [ 18 F]F " from the cyclotron. Unreacted [ 18 F]F " was efficiently removed with a Sep-Pak Alumina N cartridge. This method is also the basis for a preparation kit. An example of this method is also depicted in Figure 1. Batch results are summarized in Table 4.
• Example 2 18 F labeling of a SiFA on a commercial radiosvnthesizer (ELYXIS, Sofie
• Exemplary compound 1-Methyl-indole-SiFA was labeled with [ FJTBAF in ACN, using a commercial radiosynthesizer (ELYXIS, Sofie Biosciences).
• Example 3 One-Step-Labeling on a Batch Microfluidic Device: 18 F labeling of a SiFA on a microfluidic Teflon ® -coated chip in a true one-step radiochemical reaction under mild conditions starting with cyclotron derived
• FIG. 1 is a further graphical depiction of the process of 18 F labeling of a SiFA on a microfluidic Teflon ® - coated chip in a true one-step radiochemical reaction under mild conditions starting with cyclotron derived [ 18 F]fluoride in [ 18 0]H 2 0. Batch results are summarized in Table 5.
• Table 5 is a further graphical depiction of the process of 18 F labeling of a SiFA on a microfluidic Teflon ® - coated chip in a true one-step radiochemical reaction under mild conditions starting with cyclotron derived [ 18 F]fluoride in [ 18 0]H 2 0. Batch results are summarized in Table 5.
• Table 5 is a further graphical depiction of the process of 18 F labeling of a SiFA on a microfluidic Teflon ® - coated chip in a true one-step radiochemical reaction under mild conditions starting with cyclotron derived [ 18 F]fluoride in [ 18 0]H 2
• Example 7 TCO-SiFA as a prosthetic group for kit-like protein labeling
• TCO-SiFAs are used for example in antibody fragment-based imaging of PSCA- expressing prostate cancer ( Figure 5).
• Engineered PSCA-specific antibody fragments namely Cys-diabodies (cDb), retaining high selective binding of the parental antibody yet exhibiting rapid blood clearance, are suitable for labeling with short-lived radionuclides such as positron emitting Fluorine-18, which is achieved by click chemistry attachment of a cisDb-tetrazine derivative to a TCO-Het-SiFA.

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