WO2018207193A1 - Composés radiomarqués ciblant des transporteurs de cations organiques et leurs utilisations en radioimagerie - Google Patents

Composés radiomarqués ciblant des transporteurs de cations organiques et leurs utilisations en radioimagerie Download PDF

Info

Publication number
WO2018207193A1
WO2018207193A1 PCT/IL2018/050517 IL2018050517W WO2018207193A1 WO 2018207193 A1 WO2018207193 A1 WO 2018207193A1 IL 2018050517 W IL2018050517 W IL 2018050517W WO 2018207193 A1 WO2018207193 A1 WO 2018207193A1
Authority
WO
WIPO (PCT)
Prior art keywords
radiolabeled compound
patient
radioimaging
therapy
composition
Prior art date
Application number
PCT/IL2018/050517
Other languages
English (en)
Inventor
Eyal Yosef MISHANI
Tamar YABLONSKI-PERETZ
Ofer SHAMNI
Galith Rachel ABOURBEH-GOFRIT
Albert Hendrik GRIEVINK (Hilbert)
Original Assignee
Hadasit Medical Research Services And Development Ltd.
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 Hadasit Medical Research Services And Development Ltd. filed Critical Hadasit Medical Research Services And Development Ltd.
Publication of WO2018207193A1 publication Critical patent/WO2018207193A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/10—Quaternary compounds

Definitions

  • the present invention in some embodiments thereof, relates to radiopharmaceuticals and, more particularly, but not exclusively, to novel radiolabeled compounds that target organic cation transporters and to use thereof in radioimaging (e.g., PET or SPECT), for example, for non-invasive detection of tumors that express organic cation transporters or in myocardial perfusion imaging.
  • radioimaging e.g., PET or SPECT
  • platinum-based drugs receive platinum-based drugs, the most common being cisplatin, carboplatin and oxaliplatin. Treatment with platinum-based drugs can be associated with inherent and/or acquired resistance. All platinum compounds share four main steps in their mechanism of action; (i) cellular uptake, (ii) aquation/activation (iii) DNA platination, and (iv) cellular processing of platinum-DNA lesions, leading to cell survival or apoptosis [Johnstone et al. Anticancer Res. Jan 2014; 34(l):471-476].
  • U.S. Patent Application Publication No. 2011/0293519 discloses radiolabeled ammonium salts and uses thereof in myocardial perfusion imaging.
  • a " is an anion
  • X is selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroalicyclic and R*;
  • n is 0 or an integer of from 1 to 3;
  • n is 0 or an integer of from 1 to 4;
  • Ri and R 2 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, acrylate, methacrylate, acrylamide, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, sulfonamide, and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain of 1 to 20 carbon atoms, optionally interrupted by one or more heteroatoms, and R*; and
  • R* is a radioactive atom or a group that comprises a radioactive atom
  • X is the R*.
  • X is an alkyl, cycloalkyl, aryl or the hydrocarbon chain, which comprises one or more substituents, at least one of the substituents being the R*.
  • the radiolabeled compound is represented by Formula Pa:
  • L is the alkyl, cycloalkyl, aryl or the hydrocarbon chain or is absent; w is 0 or a positive integer;
  • q is a positive integer
  • R 3 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, acrylate, methacrylate, acrylamide, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, sulfonamide, and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain of 1 to 20 carbon atoms, optionally interrupted by one or more heteroatoms.
  • L is alkyl and R* is the radioactive atom.
  • L is absent and R* is the group that comprises the radioactive atom.
  • w 0.
  • q is 1.
  • the radioactive atom is a radioactive carbon or a radioactive halogen.
  • the radioactive atom is a radioactive halogen.
  • the radioactive halogen is fluorine- 18.
  • n and m are each 0.
  • the radiolabeled compound is:
  • F* is a radioactive fluorine
  • a pharmaceutical composition comprising as an active ingredient the radiolabeled compound as described herein in any of the respective embodiments and any combination thereof and a pharmaceutically acceptable carrier.
  • radiolabeled compound as described herein in any of the respective embodiments and any combination thereof, or a pharmaceutical composition comprising said, as described herein, for use in radioimaging.
  • the radioimaging comprises administering to a patient the radiolabeled compound or the composition and employing a nuclear imaging technique to thereby determine a presence and/or level and/or distribution of the compound in the patient's body or a portion thereof.
  • the radioimaging is for determining and/or monitoring a presence and/or level and/or distribution of an organic cation transporter within the body of the patient.
  • the radioimaging is for determining if the patient has a disease or disorder that is treatable by or responsive to a therapy whose efficacy correlates with a presence and/or level and/or distribution of an organic cation transporter (e.g., a therapy that exploits an expression and/or activity of an OCT).
  • a therapy whose efficacy correlates with a presence and/or level and/or distribution of an organic cation transporter (e.g., a therapy that exploits an expression and/or activity of an OCT).
  • the patient is diagnosed as having, or as suspected of having, the disease or disorder and the radioimaging is for determining if the disease or disorder is treatable by the therapy.
  • the radioimaging is performed following the therapy, and is for determining a responsiveness or an emergence of a resistance to the therapy.
  • the disease or disorder is a proliferative disease or disorder.
  • the radioimaging is for determining and/or monitoring a presence and/or level and/or distribution of an organic cation transporter in a tumor tissue within the body of the patient.
  • the therapy comprises a platinum-based chemotherapy.
  • the proliferative disease or disorder is metastatic colorectal cancer.
  • the method further comprising, following the first time period, determining a responsiveness or an emergence of a resistance to the therapy, the determining comprising:
  • the presence and/or level being indicative of the patient's responsiveness to the therapy
  • the radioimaging is for determining a presence and/or level of an impaired structure or function of an OCT-expressing cell, tissue and/or organ in the patient.
  • the radioimaging is for determining a presence and/or level of a disease or disorder associated with an impaired structure or function of an OCT-expressing cell, tissue and/or organ in the patient.
  • the patient is suspected as having, or has a predisposition to having, the disease or disorder.
  • the OCT-expressing cell, tissue and/or organ is a myocardial tissue, the heart muscle or a portion of the heart muscle.
  • the radioimaging is for determining a presence and/or level of a cardiovascular disease or disorder or a cardiac disease or disorder.
  • the radioimaging is myocardial perfusion imaging. According to some of any of the embodiments described herein, the radioimaging is for determining efficacy of a therapy of the disease or disorder, and/or is utilized in a treatment of the disease or disorder, as described herein.
  • the technique is positron emission tomography.
  • the technique is single photon emission computed tomography.
  • FIGs. 1A-C present plots showing time-course of [ 18 F]FEtQ uptake into HEK293 cells expressing OCT1 (FIG. 1A), OCT-2 (FIG. IB) and OCT-3 (FIG. 1C), compared to cells transfected with an Empty Vector (EV). Each experiment was repeated twice using triplicate samples. Results are presented as mean + SEM.
  • FIG. 2 is a bar graph demonstrating the inhibition of [ 18 F]FETQ cellular uptake by corticosterone in HEK293 cells stably transfected with Empty Vector or hOCT3. Each experiment was repeated twice using triplicate samples. Data is presented as the mean ⁇ SEM.
  • FIGs. 3A-B present comparative time-activity curves obtained following i.v. injection of
  • FIGs. 4A-D present representative PET/CT coronal (FIG. 4A), axial (FIG. 4B), sagittal (FIG. 4C) and maximum-intensity projection (FIG. 4D) images obtained at 25-45 minutes following injection of [ 18 F]FEtQ into a male SD rat.
  • FIGs. 6A-D present PET-CT images of a non-human primate (NHP).
  • FIGs. 7A-E present data showing in vivo uptake and blocking of [ 18 F]FEtQ.
  • FIGs. 9A-B present time-activity curves obtained following i.v. injection of [ u C]MeQ into male SD rats, in the left ventricle and liver (green triangles) (FIG. 9A), and representative PET/CT coronal, axial and sagittal images obtained at 10-25 minutes following injection of [ n C]MeQ into a male SD rat (FIG. 9B).
  • FIGs. 9A-B present time-activity curves obtained following i.v. injection of [ u C]MeQ into male SD rats, in the left ventricle and liver (green triangles) (FIG. 9A), and representative PET/CT coronal, axial and sagittal images obtained at 10-25 minutes following injection of [ n C]MeQ into a male SD rat (FIG. 9B).
  • the present invention in some embodiments thereof, relates to radiopharmaceuticals and, more particularly, but not exclusively, to novel radiolabeled compounds that target organic cation transporters and to use thereof in radioimaging (e.g., PET or SPECT), for example, for non-invasive detection of cancers that express organic cation transporters or in myocardial perfusion imaging.
  • radioimaging e.g., PET or SPECT
  • OCT organic cation transporters
  • radioactive agents that target OCTs in a patient would allow determining a presence, level and/or distribution of OCTs in the patient's body by a radioimaging technique, and would thereby provide highly useful information for determining and monitoring a suitable therapy for a medical condition in the patient, particularly in cases where the therapy correlates with intracellular accumulation of a drug.
  • the present inventors were prompt by the recognition that high OCT expressing tumors are more sensitive to treatment with platinum-based drugs, as in these tumors the OCTs play a more prominent role in the influx, accumulation, and eventual cytotoxicity of these agents.
  • the present inventors have conceived that non-invasive systemic screening of OCT-overexpressing tumors could provide information useful for devising treatment strategy, outcome prediction, and could also be employed for detecting resistance development through loss of OCT expression.
  • an OCT-targeting radiolabeled compound could be employed for imaging OCT-expressing tumors by a radioimaging technique such as PET or SPECT.
  • an OCT-targeting radiolabeled compound could be employed for imaging other OCT-expressing tissues and/or organs, by a radioimaging technique such as PET or SPECT, and that such imaging can be useful for evaluation an impaired structure and/or function of such organs and/or tissues.
  • a radioimaging technique such as PET or SPECT
  • OCTs are expressed in cardiac tissues and have thus conceived that OCT-targeting radiolabeled compounds can be a useful tool in myocardial perfusion imaging
  • the present inventors have shown that utilizing radiolabeled compounds having a quinolinium skeleton in radioimaging enables non-invasive systemic detection of OCT- expressing tumors.
  • the present inventors have prepared an exemplary fluorine- 18 labeled quinolinium salt compound, referred to herein as [ 18 F]fluoroethylquinolinium ([ 18 F]FEtQ), by a one-step radiosynthesis, and have first shown that the uptake of this compound by OCT-transfected cells is substantially higher than in empty vector cells (see, FIG. 1), and is adversely affected in the presence of an OCT inhibitor (see, FIG. 2).
  • the present inventors have conducted in vivo studies for evaluating the uptake and the clearance of this radiolabeled compound and the obtained data is presented in FIGs. 3A-C, 4A-D and 6A-D.
  • In vivo studies in the presence of an OCT inhibitor corroborated the effect of such inhibitors on the cellular uptake of the [ 18 F]FEtQ, as shown in FIGs. 5A-C and 7A-E.
  • the present inventors have further shown that utilizing radiolabeled compounds having a quinolinium skeleton enables imaging of OCT-expressing tissues such as a cardiac tissue.
  • the present inventors have shown a pronounced LV uptake of [ 18 F]FEtQ (see, FIG. 3A) and successful imaging of the LV and good contrast between the heart and its surrounding tissues in rats (see, FIGs. 4A-D).
  • the present inventors have also successfully prepared and practiced a carbon- 11 labeled quinolinium salt compound and have shown high LV uptake of this agent as well. See, FIGs. 9A-B.
  • Embodiments of the present invention therefore relate to novel radiolabeled compounds that target an OCT in a patient's body.
  • Embodiments of the present invention further relate to using such radiolabeled compounds in radioimaging, for determining a presence and/or level and/or distribution of OCTs in the patient's body, for determining a suitable therapy for the patient based on the presence and/or level and/or distribution of OCTs in the patient's body, and/or for monitoring the progress of a medical condition in the patient during or following therapy, based on the presence and/or level and/or distribution of OCTs in the patient's body; and/or for determining a condition or deterring an impaired structure and/or function of OCT- expressing tissue and/or organ.
  • Some embodiments of the present invention also relate to quinolinium-based salts which are usable in targeting an OCT.
  • a radiolabeled compound that is capable of targeting, as described and defined herein, an organic cation transporter such as a human organic cation transporter, as described and defined herein.
  • targeting an OCT it is meant that the compounds have an affinity to an OCT, and can therefore interact with an OCT.
  • This term encompasses modulation of an activity of an OCT (e.g., activating or inhibiting), interaction with an OCT by being a substrate thereof (such that an OCT facilitates influx of the compound into cells expressing the OCT), and/or simply interacting with an OCT (either chemically or physically) without affecting its activity.
  • Interacting with an OCT encompasses, for example, chemically interacting (e.g., via hydrogen bond(s) formation, covalent bond(s) formation and/or ionic bond(s) formation) with a portion of the OCT and/or an uptake by cells, tissue and/or organs which express an OCT.
  • compounds that interact with an OCT have an affinity to an OCT which is reflected by a Km value of no more than 10 micromolar, or no more than 1 micromolar, or no more than 500 nM or no more than 100 nM or of a few nM.
  • the radiolabeled compound features a skeleton that resembles a skeleton of a substrate or an inhibitor of an organic cation transporter.
  • the radiolabeled compound features a skeleton that features at least some of the structural features of a substrate or an inhibitor of an organic cation transporter.
  • the radiolabeled compound features a skeleton that resembles, or features at least some of the structural features of, an inhibitor of an organic cation transporter.
  • the inhibitor of an organic action transporter is Decynium 22 (as shown hereinabove), and the radiolabeled compound features a quinolinium salt skeleton.
  • the radiolabeled compound features a skeleton that comprises a quinolinium salt moiety that is linked to or substituted by a substituted or unsubstituted, saturated or unsaturated, moiety, for example, an aromatic moiety (aryl) or heteroaromatic moiety (heteroaryl) or cycloalkyl or heteroalicyclic, as these moieties are defined hereinunder.
  • the radiolabeled compound features a skeleton that resembles a quinolinium salt skeleton, for example, a skeleton that comprises a quaternary ammonium salt of a nitrogen-containing heterocyclic moiety other than quinoline.
  • nitrogen-containing heterocyclic moiety are encompassed heteroalicyclic and heteroaryl moieties, as defined herein, containing one or more nitrogen atoms within the cyclic ring.
  • exemplary nitrogen-containing heterocyclic moieties include, but are not limited to, imidazole, morpholine, piperidine, piperazine, oxalidine, pyrrole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, isoquinoline and purine.
  • radiolabeled compound (type specified or not) describes a compound that comprises one or more radioactive atoms, as defined herein.
  • radioactive atom describes an atom with a specific radioactivity above that of background level for that atom. It is well known, in this respect, that naturally occurring elements are present in the form of varying isotopes, some of which are radioactive isotopes. The radioactivity of the naturally occurring elements is a result of the natural distribution of these isotopes, and is commonly referred to as a background radioactive level. However, there are known methods of enriching a certain element with isotopes that are radioactive. The result of such enrichment is a population of atoms characterized by higher radioactivity than a natural population of that atom, and thus the specific radioactivity thereof is above the background level.
  • the radioactive atoms or radiolabeled compounds of the present embodiments have a specific radioactivity that is higher than the corresponding non-radioactive atoms or non- labeled compounds, respectively, and can therefore be used as agents for radioimaging and radiotherapy.
  • non-radioactive refers to an atom or a group that does not comprise a radioactive atom and thus the specific radioactivity thereof is of a background level.
  • radioactive refers to an atom or a group that comprises a radioactive atom and therefore the specific radioactivity thereof is above the background level.
  • the radioactive atom is a radioactive carbon.
  • the radioactive carbon is carbon-11, which is also referred to herein as U C or as [ U C].
  • Radioactive isotopes of carbon are also contemplated.
  • Radioactive isotopes of carbon or chemical groups comprising radioactive carbon can be commercially available, or can be generated by methods known in the art.
  • the radioactive atom is a radioactive halogen, for example, a radioactive fluorine, a radioactive bromine and/or a radioactive iodine.
  • the radioactive halogen is a radioactive fluorine.
  • the radioactive halogen is fluorine- 18, which is also referred to herein as 18 F, or as [F 18 ].
  • Fluorine- 18 radiolabeled compounds are known as useful as radioimaging agents for PET.
  • the radioactive halogen is a radioactive bromine.
  • Exemplary radioactive bromine atoms include, but are not limited to, bromine-76 and bromine-77.
  • Bromine-76 radiolabeled compounds are usable in PET radioimaging.
  • the radioactive halogen is a radioactive iodine.
  • radioactive iodine atoms include, but are not limited to, iodine-123, iodine- 124, and iodine- 131.
  • Iodine-123 radiolabeled compounds are usable in SPECT radioimaging.
  • Iodine- 124 radiolabeled compounds are usable in both PET radioimaging and/or radiotherapy.
  • Radioactive isotopes of fluorine, bromine and iodine are also contemplated. Radioactive isotopes of fluorine, bromine and iodine can be commercially available, or can be generated by methods known in the art.
  • radiolabeled compounds featuring a quinolinium salt skeleton which are collectively represented by Formula P:
  • a " is an anion, as defined and described herein;
  • X is selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroalicyclic and R*;
  • n is 0 or an integer of from 1 to 3;
  • n is 0 or an integer of from 1 to 4;
  • Ri and R 2 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, acrylate, methacrylate, acrylamide, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, sulfonamide, and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain of 1 to 20 carbon atoms, optionally interrupted by one or more heteroatoms, and R*;
  • R* is a radioactive atom or a group that comprises a radioactive atom, and provided that at least one of Ri, R 2 and X is R*, such that the compound comprises one or more radioactive atoms.
  • a radiolabeled compound of Formula I* of the present embodiments can feature a radioactive atom that is or forms a part of a substituent of a carbon atom of the quinolinium salt (one or more of Ri and R 2 ) and/or a radioactive atom that is or forms a part of a substituent of the nitrogen atom of the quinolinium salt (X).
  • one or more of Ri and R 2 is R*.
  • a radioactive atom is or forms a part of any of the groups defining Ri and R 2 .
  • X is R*.
  • a radioactive atom is or forms a part of any of the groups defining X.
  • the radioactive carbon can be a carbon of any of the groups defining X.
  • X is an alkyl, cycloalkyl, aryl or the hydrocarbon chain, as defined herein, in which one of the carbon atoms is a radioactive carbon.
  • X is alkyl, such as a lower alkyl, of 1-10, or of 1-8, or of 1-6, or of 1-5, or of 1-4, or of 1-3, or of 1-2, carbon atoms, one of the carbon atoms be a radioactive carbon as described herein.
  • X is methyl
  • the carbon atom is a radioactive carbon (e.g., carbon- 11).
  • the alkyl is an unsubstituted alkyl.
  • the alkyl is substituted by any of the substituents defined herein.
  • radioactive atom is a radioactive halogen
  • the radioactive halogen can be, for example, a substituent of an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or a hydrocarbon chain defining X.
  • L is the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or the hydrocarbon chain defining X in Formula P, as defined herein;
  • w is 0 or a positive integer
  • q is a positive integer
  • R 3 which represents optional other, non-radioactive, substituents of the alkyl, cycloalkyl, aryl or hydrocarbon chain, can be one or more of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, acrylate, methacrylate, acrylamide, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, sulfonamide, and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain
  • R* in Formula Pa is as defined herein for R* in Formula P.
  • L is an alkyl, alkenyl, alkynyl, cycloalkyl or aryl, which is substituted by the radioactive atom (e.g., a radioactive halogen).
  • R* in Formula Pa is the radioactive atom (e.g., a radioactive halogen).
  • L is an alkyl, alkenyl, alkynyl, cycloalkyl or aryl, which is substituted by a group that comprises (e.g., is substituted by) the radioactive atom (e.g., a radioactive halogen).
  • R* in Formula Pa is a group that comprises the radioactive atom (e.g., the radioactive halogen).
  • L is alkyl, such as a lower alkyl, of 1-10, or of 1-8, or of 1-6, or of 1-5, or of 1-4, or of 1-3, or of 1-2, carbon atoms, and R* is a substituent of the alkyl.
  • R* is a radioactive halogen substituting the alkyl.
  • w 0.
  • q is 1.
  • the radioactive atom is a radioactive halogen.
  • the radioactive halogen is fluorine - 18.
  • n 0.
  • n and m are each 0.
  • R* is a hydrocarbon chain, as defined herein, which is substituted or terminated by a radioactive atom (e.g., a radioactive halogen).
  • a radioactive atom e.g., a radioactive halogen
  • hydrocarbon describes an organic moiety that includes, as its basic skeleton, a chain of carbon atoms, also referred to herein as a backbone chain, substituted mainly by hydrogen atoms.
  • the hydrocarbon can be saturated or unsaturated, be comprised of aliphatic, alicyclic and/or aromatic moieties, and can optionally be substituted by one or more substituents (other than hydrogen).
  • a substituted hydrocarbon may have one or more substituents, whereby each substituent can independently be, for example, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine, and any other substituents as described herein (for example, as defined herein for Ri and R 2 ).
  • substituents can independently be, for example, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulf
  • the hydrocarbon moiety can optionally be interrupted by one or more heteroatoms, including, without limitation, one or more oxygen, nitrogen (substituted or unsubstituted, as defined herein for - NR'-) and/or sulfur atoms.
  • the hydrocarbon is not interrupted by any heteroatom, nor does it comprise heteroatoms in its backbone chain, and can be an alkylene chain, or be comprised of alkyls, cycloalkyls, aryls, alkaryls, aralkyls, alkenes and/or alkynes, as defined herein, covalently attached to one another in any order.
  • the hydrocarbon chain is such that one or more of the groups composing the backbone chain, as described herein, is substituted by a radioactive halogen.
  • the hydrocarbon is such that a terminal group in the backbone chain, for example, an alkyl, alkenyl or alkynyl, is substituted at its terminus by a radioactive halogen.
  • R* in Formula Pa is or comprises an alkylene chain as defined herein.
  • L in Formula Pa is an alkylene chain as defined herein.
  • alkylene describes a saturated aliphatic hydrocarbon group, as this term is defined herein. This term is also referred to herein as “alkyl”.
  • one or more carbon atoms in the alkylene chain is substituted by a radioactive halogen.
  • the terminal carbon in the alkylene (at the distal end relative to the point of its attachment to the quinolinium ring) is substituted by a radioactive halogen.
  • R* when R* is an alkylene chain, R* can be represented by (CR'R")nV*, wherein R' and R" are as defined herein, and each independently can be, for example, hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, and sulfonamide; n is an integer of from 2 to 20; and V* is the radioactive halogen.
  • R* is an alkylene chain that is composed of 2-20
  • R' and R" in each of these units can independently be the same or different.
  • each of R' and R" is hydrogen.
  • R* is an unsubstituted alkylene chain that terminates with a radioactive halogen.
  • R* can represent a substituted alkylene chain that terminates with a radioactive halogen.
  • n is an integer ranging from 1 to 10, or from 1 to 6, or from 1 to 4.
  • n 1 or 2.
  • the hydrocarbon chain is interrupted by one or more heteroatoms.
  • Exemplary such hydrocarbons comprise one or more alkylene glycol groups or derivatives thereof.
  • alkylene glycol describes a -[0-(CR'R")z]y- group, with R' and R" being as defined herein (and/or as defined herein for Ri and R 2 ), and with z being an integer of from 1 to 10, preferably, from 2 to 6, more preferably 2 or 3, and y being an integer of 1 or more.
  • R' and R" are both hydrogen.
  • z is 2 and y is 1, this group is ethylene glycol.
  • z is 3 and y is 1, this group is propylene glycol.
  • y is greater than 1, this group is also referred to herein as "alkylene glycol chain”.
  • a poly(alkylene glycol) moiety can have from 4 to 10 alkylene glycol groups, such that y is, for example, 4 to 10.
  • the hydrocarbon chain is or comprises one or more alkylene glycol derivatives, in which one or more of the oxygen atoms is replaced by a sulfur atom and/or a -NR'- group, as defined herein, and/or one or more of R' and R" in one or more unit is other than hydrogen.
  • R* is or comprises one or more alkylene glycol groups, as defined herein, and terminates with a radioactive halogen, as described herein, such that a radioactive halogen is attached to the alkylene glycol group or to a terminal alkylene glycol group in case where y is greater than 1.
  • R' and R" in one of the one or more alkylene glycol groups is a radioactive halogen.
  • the number of alkylene glycol groups can range from 1 to 20, or from 1 to 10, or from 1 to 8, or from 1 to 6, or from 1 to 4, or from 1 to 3, or from 1 to 2.
  • the groups can be the same or different.
  • R' and R" in each of these groups can independently be the same or different.
  • one or more alkylene glycol groups can differ from one another when one or both of the oxygen atoms is replaced by -NR'- or -S- in one or more units.
  • R' and R' ' are each hydrogen.
  • each of R' and R" is hydrogen.
  • R* is or comprises an unsubstituted alkylene glycol chain that terminates with a radioactive halogen.
  • one or both of R' and R' ' in one of more of the alkylene glycol groups is other than hydrogen, and R* is or comprises a substituted alkylene glycol chain that terminates with a radioactive halogen.
  • the hydrocarbon moiety has from 2 to 20 carbon atoms, or 2 to 10 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • the radioactive atom is a radioactive carbon, which replaces one or more the carbon atoms in the hydrocarbon chain or in a substituent thereof.
  • the hydrocarbon chain does not comprise a radioactive halogen.
  • the radiolabeled compound is: wherein A- is an anion as defined herein and R* is a radioactive halogen as defined herein.
  • the radioactive halogen is radioactive fluorine such as fluorine- 18.
  • An exemplary such compound is also referred to herein as [ 18 F]-fluoroethyl quinolinium salt is represented by the formula:
  • A- is an anion as defined herein and R* is a radioactive fluorine such as fluorine- 18.
  • the radiolabeled compound is:
  • A- is an anion as defined herein, and wherein *C is a radioactive carbon such as carbon- 11.
  • the anion, denoted as A " in the quaternary ammonium salt can be any stable negatively charged atom or group.
  • a " is a conjugated base of an acid, wherein the acid can be an organic acid or an inorganic acid.
  • Exemplary anions include, but are not limited to, sulfonate, such as benzenesulfonate (besylate), methanesulfonate (mesylate), toluene sulfonate (tosylate), trifluoromethanesulfonate (triflate) and naphthalenesulfonate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, nitrate, phosphate, phosphonate, metaphosphate, pyrophosphate, halide (e.g., chloride, bromide, iodide), and a carboxylate such as, but not limited to, acetate, trifluoroacetate, ascorbate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenz
  • a " is a sulfonate, which can be derived from an organic or inorganic sulfonic acid.
  • Exemplary such anions include, but are not limited to, benzenesulfonate, toluenesulfonate (tosylate), trifluoromethanesulfonate (triflate) and methanesulfonate (mesylate).
  • a " is a halide, preferably iodide.
  • a radiolabeled compound as described herein is capable of, or is characterized as being capable of, or is usable in, targeting, as defined herein, an organic cation transporter (OCT) as described herein in any of the respective embodiments.
  • OCT organic cation transporter
  • the targeting of a radiolabeled compound as described herein is reduced in the presence of an inhibitor or substrate of the OCT.
  • a radiolabeled compound as described herein has an affinity to an organic cation transporter as described herein in any of the respective embodiments, whereby the affinity is characterized by, ideally, a Km value of no more than 10 micromolar, or no more than 1 micromolar, or no more than 500 nM, or no more than 100 nM, or of a few nM.
  • the affinity of the radiolabeled compound to an OCT as defined herein can be determined by methods known in the art. An exemplary method is described in the Examples section that follows.
  • non- radiolabeled compounds which are usable in targeting an OCT, or which are for use in targeting an OCT, as defined herein.
  • the OCT is as defined herein.
  • non-radiolabeled compounds which are usable for targeting an OCT, are collectively represented by Formula la:
  • a " is an anion, as defined and described herein;
  • n is 0 or an integer of from 1 to 3;
  • n is 0 or an integer of from 1 to 4;
  • w is 0 or a positive integer
  • L is selected from an alkyl, alkaryl, alkenyl, alkynyl, aryl, heteroalicyclic, heteroaryl and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain of 1 to 20 carbon atoms, optionally interrupted by one or more heteroatoms;
  • R 3 is a substituent of said L, and is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, acrylate, methacrylate, acrylamide, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, sulfonamide, and a substituted or unsubstituted, a saturated or unsaturated hydrocarbon chain of 1 to 20 carbon atoms, optionally interrupted by one or more heteroatoms; and Ri and R
  • L is an alkyl or is a hydrocarbon chain as described herein.
  • L is an alkyl, and in some embodiments it is an unsubstituted alkyl, for example, a lower alkyl as defined herein. In exemplary embodiments, L is methyl.
  • L is an alkyl, for example, a lower alkyl as defined herein, and in some embodiments, the alkyl is substituted by one or more halogen substituents. In some embodiments, the alkyl is substituted by a fluoro substituent, and in some embodiments, the alkyl terminates by a fluoro substituent.
  • a " is an anion as described and defined herein.
  • radiolabeled compounds as described herein are readily synthesizable, using, for example, one-step radiosyntheses.
  • a process of preparing a radiolabeled compound as described herein is effected by introducing a radioactive atom or a group that comprises a radioactive atom to a quinolinium salt.
  • Routes for introduction of a radioactive atom or a group comprising same can be selected using methodologies used in the art, depending on the position and chemical nature of the radioactive atom or group.
  • the process is effected by reacting a compound of Formula P, in which there is a leaving group instead of the radioactive halogen, with a radioactive atom or a reagent generating same, for example, M + Z " , wherein M + is a cation of an alkali metal and Z " is a radioactive halide anion from which a radioactive atom is generated.
  • the phrase "leaving group” describes a labile atom, group or chemical moiety that readily undergoes detachment from an organic molecule during a chemical reaction, while the detachment is facilitated by the relative stability of the leaving atom, group or moiety thereafter.
  • any group that is the conjugate base of a strong acid can act as a leaving group.
  • Suitable leaving groups therefore include, without limitation, carboxylate (e.g., acetate), thiocarboxylate, sulfate (e.g., tosylate, mesylate), sulfonate (e.g., triflate), sulfinate, thiosulfate, thio sulfonate, thiosulfinate, sulfoxide, alkoxy, halogen (preferably bromo or iodo), amine, sulfonamide, carbamate, thiocarbamate, azide, phosphonyl, phopshinyl, phosphate, cyanate, thiocyanate, nitro and cyano, as these terms are defined herein.
  • carboxylate e.g., acetate
  • thiocarboxylate e.g., tosylate, mesylate
  • sulfonate e.g., triflate
  • sulfinate
  • the leaving group that is replaced by the radioactive atom forms that A " anion in the salt.
  • a radioactive halide of choice e.g., [ 18 F] "
  • [ 76 Br] " , [ 77 Br] " , [ 123 I] , [ 124 I] " or [ 131 I] " can be generated by methods known in the art, or can be purchased from known vendors, either per se, or as a reagent generating same (for example, M + Z " , as described herein).
  • radiolabeled compounds herein described can be used as radioimaging agents. Fluorine- 18 labeled, carbon- 11 labeled, bromine-76 labeled and iodine- 124 labeled compounds of the present embodiments can be used as biomarkers for PET radioimaging, whereas iodine - 123 labeled compounds of the present embodiments, can be used as biomarkers for SPECT radioimaging.
  • the radiolabeled compounds as described herein are for use in radioimaging, or in a method of radioimaging, or as radioimaging agents.
  • the radiolabeled compounds as described herein are for use in the manufacture of a radioimaging agent.
  • the radioimaging agent is for use in a method of radioimaging as described herein.
  • a method radioimaging which comprises administering to a patient in need thereof a radiolabeled compound that targets an organic cation transporter and employing a suitable nuclear imaging technique, such as positron emission tomography or single photon emission computed tomography, for monitoring a presence and/or a level and/or a distribution and/or a distribution rate of the radiolabeled compound within the body or within a portion thereof.
  • a suitable nuclear imaging technique such as positron emission tomography or single photon emission computed tomography
  • an "organic cation transporter”, abbreviated as OCT, describes an organic cation transporter of the solute carrier SLC22A family, as described herein and in the art, which facilitates the intracellular uptake of a broad range of structurally diverse, small organic cations.
  • the organic cation transporter is a human OCT (hOCT), and encompasses currently identified human OCT isoforms such as, but not limited to, OCTl, which is encoded by SLC22A1; OCT2, which is encoded by SLC22A2; and OCT3, which is encoded by SLC22A3.
  • hOCT human OCT
  • OCT Any OCT that can be expressed in a subject as defined herein, e.g., a human being, is contemplated.
  • the targeting of an OCT can be determined by cellular uptake of the radiolabeled compound and/or by its affinity to the OCT and/or by an effect of a known substrate or inhibitor of the OCT on the cellular uptake of the radiolabeled compound.
  • the radioimaging is effected by administering to the patient a radiolabeled compound and employing a suitable nuclear imaging technique, such as positron emission tomography or single photon emission computed tomography, for monitoring a presence and/or level and/or distribution and/or the distribution rate of the radiolabeled compound within the body or within a portion thereof.
  • a suitable nuclear imaging technique such as positron emission tomography or single photon emission computed tomography
  • the radiolabeled compound is a fluorine- 18, carbon- 11, bromine-76, iodine- 123 or iodine- 124 radiolabeled compound.
  • the radiolabeled compound is a fluorine- 18, carbon- 11, bromine-76, iodine- 123 or iodine- 124 radiolabeled compound as described herein in any of the respective embodiments, or any other radiolabeled compound that comprises a radioactive atom suitable for nuclear imaging and is capable of targeting an OCT as defined herein.
  • a method of radioimaging which comprises administering to the patient any of, for example, the fluorine- 18, carbon-11, bromine-76, iodine- 123 or iodine- 124 radiolabeled compounds as described herein in any of the respective embodiments and employing a suitable nuclear imaging technique, such as positron emission tomography or single photon emission computed tomography, for monitoring a presence and/or level and/or distribution and/or distribution rate of the radiolabeled compound within the body or within a portion thereof.
  • a suitable nuclear imaging technique such as positron emission tomography or single photon emission computed tomography
  • Nuclear imaging dosing depends on the affinity of the compound to its target, the isotope employed and the specific activity of labeling. Persons ordinarily skilled in the art can easily determine optimum nuclear imaging dosages and dosing methodology.
  • a radioimaging method as described herein is useful for monitoring or determining a presence and/or level and/or distribution of an OCT within the body of the patient.
  • the radiolabeled compounds as described herein are preferably characterized by at least a moderate affinity to OCT.
  • Cells, tissues or organs which feature an increased expression of OCT are therefore assumed to result in a higher uptake of the radiolabeled compounds of the present embodiments, compared to those which do not feature overexpression of OCT, such that an accumulation (presence and level) of the radiolabeled compound at certain cells, tissues and or organs of a patient (distribution) is indicative of an increased expression of OCT in these cells.
  • the presence and/or level and/or distribution of the radiolabeled compound in the patient's body or a portion thereof is indicative of subject's medical condition in case this condition is associated with deregulated expression and/or activity of an OCT; and/or is treatable by modulating an expression and/or activity of an OCT; and/or is treatable by an agent that exploits an expression and/or activity of an OCT.
  • the radioimaging is for determining if the patient has a disease or disorder that is treatable by modulating an expression and/or activity of an organic cation transporter.
  • Such a radioimaging is useful for determining if the patient suffers from a disease or disorder that is associated with deregulated activity and/or expression of an OCT and/or which is treatable by modulating an activity of an OCT.
  • deregulated activity and/or expression of an OCT describes aberrant, or abnormal, activity and/or expression of OCT, for example, overexpression of OCT, overactivity of OCT or reduced activity of OCT.
  • the radioimaging is for determining if the patient has a disease or disorder treatable by an agent that modulates the expression and/or activity of an OCT.
  • the radioimaging is for determining if the patient has a disease or disorder treatable by an agent that modulates an activity of an OCT, for example by an inhibitor, an activator or a substrate of an OCT.
  • the radioimaging is for determining if the patient is responsive to a treatment with an agent that modulates an activity and/or expression of an OCT.
  • the patient is diagnosed as having a disease or disorder associated with deregulated expression and/or activity of OCT, and the radioimaging is for determining if the patient should be treated with an agent that modulates an activity and/or expression of an OCT.
  • any agents that modulate an activity and/or expression of an OCT such as, for example, inhibitors, activators and substrates of OCTs (e.g., hOCTs) known in the art are contemplated herein.
  • radioimaging a method of radioimaging, or a use of the radiolabeled compounds as described herein in radioimaging, as described herein, and the radioimaging is for determining if a patient is responsive to a treatment with an agent that modulates an activity of an OCT.
  • such a method is suitable for determining a first-line therapy for a patient who is diagnosed as having, or as suspected of having, a disease or disorder associated with deregulated expression and/or activity of OCT.
  • the radioimaging is for determining if the patient has a disease or disorder that is treatable by exploiting an expression and/or activity of an organic cation transporter.
  • Such a radioimaging is useful for determining if the patient suffers from a disease or disorder that is treatable by exploiting an expression and/or an activity of an OCT.
  • the radioimaging is for determining if the patient has a disease or disorder treatable by an agent that interacts (e.g., taken up) with an OCT, as defined herein, for example, a therapeutically active agent (drug) that is positively charged and its intracellular accumulation is effected by an expression and/or activity of OCT (e.g., in a certain cell, tissue or organ).
  • an agent that interacts e.g., taken up
  • an OCT e.g., a therapeutically active agent (drug) that is positively charged and its intracellular accumulation is effected by an expression and/or activity of OCT (e.g., in a certain cell, tissue or organ).
  • the radioimaging is for determining if the patient is responsive to a treatment with an agent that exploits an activity and/or expression of an OCT.
  • the radioimaging is for determining if the patient is responsive to a treatment with an agent that interacts with an OCT (e.g., taken up by an OCT).
  • an OCT e.g., taken up by an OCT
  • radioimaging a method of radioimaging, or a use of the radiolabeled compounds as described herein in radioimaging, as described herein, and the radioimaging is for determining if a patient is responsive to a treatment with an agent that exploits an activity of an OCT, as described herein.
  • the presence and/or level and/or distribution of the radiolabeled compound in the patient's body or a portion thereof is indicative of the responsiveness of the patient's to a therapy whose efficacy correlates with a presence and/or level of an organic cation transporter.
  • the radioimaging is for determining if the patient has a disease or disorder that is treatable by or responsive to a therapy whose efficacy correlates with a presence and/or level and/or distribution of an organic cation transporter.
  • the patient is diagnosed as having, or as suspected of having, a disease or disorder that is treatable by or responsive to a therapy whose efficacy correlates with a presence and/or level and/or distribution of an organic cation transporter and the radioimaging is for determining if the disease or disorder is treatable by the therapy.
  • a therapy that correlates with a presence and/or level and/or distribution of an organic cation transporter encompasses a therapy that comprises, or consists of, administration of a therapeutically active agent (drug) and its efficacy depends on a level of intracellular accumulation of the drug, at least to certain cells.
  • the radioimaging is performed following the therapy, and is for determining a responsiveness or an emergence of a resistance to the therapy.
  • the disease or disorder is a proliferative disease or disorder.
  • the patient is diagnosed as having, or as suspected of having, a proliferative disease or disorder such as cancer.
  • a patient is diagnosed, or is suspected to be diagnosed, with the indicated disease or disorder, by means known in the art, such as, for example, imaging methods such as computed tomography (CT), MRI, X-ray imaging, and/or by means of biopsy, determination of biomarkers in blood samples, etc.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • X-ray imaging X-ray imaging
  • the radioimaging is for determining and/or monitoring a presence and/or level and/or distribution of an organic cation transporter in a tumor cell or tissue within the body of the patient.
  • cancer and “tumor” are interchangeably used.
  • the terms refer to a malignant growth and/or tumor caused by abnormal and uncontrolled cell proliferation (cell division).
  • cancer encompasses tumor metastases.
  • cancer cells describes the cells forming the malignant growth or tumor.
  • Non-limiting examples of cancers and/or tumor metastases preferably include solid cancer and/or tumor metastasis, including, but not limiting to, tumors of the gastrointestinal tract (e.g., colon carcinoma, rectal carcinoma, colorectal carcinoma, colorectal cancer, colorectal adenoma, hereditary nonpolyposis type 1, hereditary nonpolyposis type 2, hereditary nonpolyposis type 3, hereditary nonpolyposis type 6; colorectal cancer, hereditary nonpolyposis type 7, small and/or large bowel carcinoma, esophageal carcinoma, tylosis with esophageal cancer, stomach carcinoma, pancreatic carcinoma, pancreatic endocrine tumors), endometrial carcinoma, dermatofibro sarcoma protuberans, gallbladder carcinoma, biliary tract tumors, prostate cancer, prostate adenocarcinoma, renal cancer (e.g., Wilms' tumor type 2 or type 1), liver cancer (e
  • the proliferative disease or disorder is a colorectal cancer (CRC). In some embodiments, the proliferative disease or disorder is metastatic CRC.
  • the proliferative disease or disorder is a cancer for which a first- line or second-line therapy comprises a platinum-based chemotherapy.
  • OCTs affect the cellular accumulation of platinum-based drugs
  • determining a presence and/or level and/or distribution of OCTs in, for example, tumor cells can be beneficially used for devising a treatment strategy, for monitoring treatment, for predicting an outcome of a treatment, and for identifying resistance to treatment.
  • a therapy whose efficacy that correlates with a presence and/or level of OCT in the tumor cells is a therapy comprises a platinum-based chemotherapy.
  • the therapy can consist of a platinum-based chemotherapy, or can comprise a platinum- based chemotherapy in combination with other chemotherapies and/or other therapeutic methodologies (e.g., surgery, immunotherapy, etc.).
  • Platinum-based chemotherapy encompasses administration of one or more platinum- based drugs, including, for example, cisplatin, carboplatin and oxaliplatin.
  • the platinum-based chemotherapy comprises administration of oxaliplatin.
  • the radioimaging is for monitoring or determining a presence and/or level of OCT in a patient that has been diagnosed as having a cancer for which a first- line or second-line therapy comprises a platinum-base chemotherapy.
  • a method of radioimaging or a use of the radiolabeled compounds as described herein in radioimaging, or as radioimaging agents, as described herein, and the radioimaging is for monitoring or determining a presence and/or level of OCT in a patient that has been diagnosed as having a cancer for which a first-line or second-line therapy comprises a platinum-base chemotherapy.
  • the patient is diagnosed (or is suspected to be diagnosed) with such a cancer, and the radioimaging is used for determining a suitable treatment for this patient.
  • a presence and/or level and/or distribution of the radiolabeled compound in the patient's body or the portion thereof is indicative of a presence and/or level and/or distribution of OCT which confers sensitivity to a therapy as described herein.
  • an absence of the compound in the tumor cells or tissue in the patient's body is indicative of cancer cells that do not express OCT, and suggests of a reduced sensitivity of the cancer cells to platinum-based chemotherapy, or of a resistance to platinum- based chemotherapy.
  • radiolabeled compounds as described herein are therefore useful for determining if a patient has OCT-expressing tumor cells which confer sensitivity and responsiveness to a therapy that comprises platinum-based chemotherapy.
  • the presence or absence of OCT-expressing tumor cells is determined and therapy that is suitable for treating the cancer is determined accordingly, as described herein.
  • the presence and/or level and/or distribution of the radiolabeled compound is indicative of a presence and/or level and/or distribution of OCT-expressing cancer cells, which in turn confers sensitivity to a therapy that comprises platinum-based chemotherapy, and hence of a patient being responsive to such a therapy.
  • the radioimaging is performed following a therapy as described herein (e.g., a therapy that comprises platinum-based chemotherapy), and is for determining an emergence of a resistance to the therapy.
  • an absence of the radiolabeled compound in the patient's body or a portion thereof is indicative of insensitivity (non-responsiveness) or resistance to the therapy.
  • a method of radioimaging as described herein in any of the respective embodiments is useful in the course of treatment of a patient diagnosed with a disease or disorder which is treatable by a therapy whose efficacy correlates to a level and/or presence of an organic cation transporter, as described herein.
  • a method of treating a patient diagnosed with a disease or disorder which is treatable by a therapy whose efficacy correlates to a level and/or presence of an organic cation transporter, as described herein.
  • the treatment comprises:
  • the patient is identified as responsive to the therapy, as described herein, and is subjected to the therapy.
  • the patient is indentified as non-responsive to the therapy and is subjected to another therapy of choice.
  • the patient is identified as responsive to the therapy, as described herein, and is subjected to the therapy for a first time period, and, following the first time period, a responsiveness or an emergence of a resistance to the therapy is determined by:
  • the nuclear imaging technique second radioimaging
  • the second radioimaging is preferably the same as the first radioimaging.
  • the patient is subjected to the therapy for an additional (second) time period, if it is determined that that the patient is still responsive to the therapy, or is subjected to another therapy of choice for the second time period, namely, the treatment is replaced.
  • the radioimaging can be repeated following the second time period, and following additional time periods, as long as it is determined that the patient remains responsive to the therapy.
  • Such embodiments relate to a method of treating a disease or disorder as described herein, while selecting a therapy of choice and while optionally longitudinally monitoring the therapy's efficiency, namely monitoring the patient's responsiveness to the therapy.
  • the radioimaging performed following the first time period can provide information on the treatment efficacy, and can be used for determining the therapy of choice in the second treatment period.
  • the treatment described herein therefore provides immediate indication of the treatment efficacy, and hence immediate personalized adjustment of the therapy during treatment.
  • other diagnosis measures are applied, such as biopsy, as complementary measures for verifying, supporting, and/or providing further information on top of, the radioimaging findings.
  • the method as described herein is for radioimaging OCT-expressing cells, tissues and/or organs, while exploiting an uptake of a radiolabeled compound by these cells, tissues and/or organs for gaining an information of a presence or absence of a medical condition that is associated with impaired function and/or structure of these cells, tissues and/or organs.
  • the radioimaging is of an OCT-expressing cell, tissue and/or organ and is for determining if the patient has, or is prone or predisposed to have, an impaired function and/or structure of the cell, tissue and/or organ.
  • the radioimaging is of an OCT-expressing cell, tissue and/or organ and is for determining if the patient has, or is prone or predisposed to have, a disease or disorder that is associated with impaired function and/or structure of the cell, tissue and/or organ.
  • the OCT-expressing cell, tissue and/or organ is of the cardiovascular system.
  • it is a cardiac or myocardial cell and/or tissue, and is some embodiments it is the heart muscle or a portion thereof (e.g., a left ventricle, a right ventricle, a right auricle, a left auricle).
  • it is the left ventricle (LV).
  • the OCT-expressing cell, tissue and/or organ is of the cardiovascular system, as described herein, and the radioimaging is for determining if a patient has, or is prone or predisposed to have, an impaired function and/or structure of the cardiovascular system, for example, an impaired cardiac function or impaired myocardial blood perfusion.
  • the OCT-expressing cell, tissue and/or organ is of the cardiovascular system, as described herein, and the radioimaging is for determining of a patient has, or is prone or predisposed to have, a cardiovascular disease or disorder or cardiac disease or disorder.
  • Cardiovascular diseases and disorders include, but are not limited to, atherosclerosis, a cardiac valvular disease, coronary stenosis, restenosis, in-stent-stenosis, myocardial infarction, coronary arterial disease (CAD), acute coronary syndromes, congestive heart failure, angina pectoris, myocardial ischemia, thrombosis, Wegener's granulomatosis, Takayasu's arteritis, Kawasaki syndrome, anti-factor VIII autoimmune disease or disorder, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis, antiphospholipid syndrome, antibody induced heart failure, thrombocytopenic purpura, autoimmune hemolytic anemia, cardiac autoimmunity, Chagas' disease or disorder, and anti-helper T lymphocyte autoimmunity.
  • CAD coronar
  • cardiac diseases or disorders include cardiac arrhythmi, and medical conditions associated with cardiac arrhythmia.
  • the cardiac arrhythmia can be a ventricular arrhythmia, an atrial arrhythmia, a junctional arrhythmia and a heart block.
  • Atrial arrhythmia Medical conditions associated with atrial arrhythmia include, but are not limited to, Premature atrial contractions (PACs), Wandering atrial pacemaker, Atrial tachycardia, Multifocal atrial tachycardia, Supraventricular tachycardia (SVT), Atrial flutter, and Atrial fibrillation (Afib).
  • PACs Premature atrial contractions
  • Atrial tachycardia Multifocal atrial tachycardia
  • SVT Supraventricular tachycardia
  • Atrial flutter Atrial fibrillation
  • junctional arrhythmia Medical conditions associated with junctional arrhythmia include, but are not limited to, AV nodal reentrant tachycardia, Junctional rhythm, Junctional tachycardia, and Premature junctional contraction. Medical conditions associated with ventricular arrhythmia include, but are not limited to, Premature ventricular contractions (PVCs), sometimes called ventricular extra beats (VEBs), Premature ventricular beats occurring after every normal beat are termed "ventricular bigeminy”, Accelerated idioventricular rhythm, Monomorphic ventricular tachycardia, Polymorphic ventricular tachycardia, Ventricular fibrillation, and Torsades de pointes.
  • PVCs Premature ventricular contractions
  • VEBs ventricular extra beats
  • Premature ventricular beats occurring after every normal beat are termed "ventricular bigeminy”
  • Accelerated idioventricular rhythm Monomorphic ventricular tachycardia
  • Polymorphic ventricular tachycardia Ven
  • Medical conditions associated with heart block include, but are not limited to, AV heart blocks, which arise from pathology at the atrioventricular node, including First degree heart block, which manifests as PR prolongation, Second degree heart block, including Type 1 Second degree heart block, also known as Mobitz I or Wenckebach, and Type 2 Second degree heart block, also known as Mobitz II, and Third degree heart block, also known as complete heart block.
  • First degree heart block which manifests as PR prolongation
  • Second degree heart block including Type 1 Second degree heart block, also known as Mobitz I or Wenckebach
  • Type 2 Second degree heart block also known as Mobitz II
  • Third degree heart block also known as complete heart block.
  • Exemplary medical conditions associated with cardiac arrhythmia include, but are not limited to, atrial fibrillation, ventricular fibrillation, conduction disorders, premature contraction, and tachycardia.
  • Conduction disorders collectively encompass abnormal or irregular progression of electrical pulses through the heart, which cause a change in the heart rhythm.
  • Conductions disorders are not necessarily associated with arrhythmia but sometimes are the cause of arrhythmia.
  • Exemplary conductions disorders include, but are not limited to, Bundle Branch Block, heart block, including first-, second- and third-degree heart block, and long Q-T syndrome.
  • Premature contraction includes premature atrial contractions and premature ventricular contractions.
  • Additional exemplary medical conditions associated with arrhythmia include Adams- Stokes Disease (also called Stokes-Adams or Morgangni), atrial flutter, which is usually found in patients with: Heart failure, Previous heart attack, Valve abnormalities or congenital defects, High blood pressure, Recent surgery, Thyroid dysfunction, Alcoholism (especially binge drinking), Chronic lung disease, Acute (serious) illness, Diabetes, after open-heart surgery (bypass surgery), or atrial fibrillation; Sick Sinus syndrome; sinus arrhythmia and Wolff- Parkinson-White (WPW) syndrome.
  • Adams- Stokes Disease also called Stokes-Adams or Morgangni
  • atrial flutter which is usually found in patients with: Heart failure, Previous heart attack, Valve abnormalities or congenital defects, High blood pressure, Recent surgery, Thyroid dysfunction, Alcoholism (especially binge drinking), Chronic lung disease, Acute (serious) illness, Diabetes, after open-heart surgery (bypass surgery), or atrial fibrillation
  • Sick Sinus syndrome sinus
  • the cardiac arrhythmia can include tachycardia, and encompasses atrial and
  • Supraventricular tachycardia including paroxysmal atrial tachycardia (PAT) or paroxysmal supraventricular tachycardia (PSVT);
  • Sinus tachycardia which can be associated with disorders of that heart which interfere with the normal conduction system of the heart, including, but not limited to, Lack of oxygen to areas of the heart due to lack of coronary artery blood flow, Cardiomyopathy in which the structure of the heart becomes distorted, Medications, Illicit drugs such as cocaine, and Sarcoidosis (an inflammatory disease affecting skin or other body tissues).
  • the tachycardia can be a ventricular tachycardia, a supraventricular tachycardia, atrial fibrillation, AV nodal reentrant tachycardia (AVNRT), or a AV reentrant tachycardia (AVRT).
  • APNRT AV nodal reentrant tachycardia
  • AVRT AV reentrant tachycardia
  • Additional cardiac diseases and disorders include CPVT, long QT syndrome, bradycardia and diseases and disorders associated with bradycardia.
  • the radioimaging is a myocardial perfusion imaging (MPI), which is for determining a function of the heart, its structure and/or blood perfusion into the heart.
  • MPI myocardial perfusion imaging
  • Myocardial perfusion imaging is currently the most common tool for non-invasively evaluating ischemia in patients with suspected coronary artery disease (CAD).
  • CAD coronary artery disease
  • This technique contributes substantially to the risk- stratification of CAD patients, in terms of their likelihood to encounter myocardial or coronary events such as myocardial infarction, myocardial ischemia, coronary aneurysm, wall motion abnormalities; to the assessment of a viable myocardium following a coronary event when revascularization is considered; and to an assessment of the myocardium following intervening revascularization (e.g., coronary artery bypass graft, angioplasty).
  • coronary artery bypass graft angioplasty
  • MPI provides valuable information which assists clinical decision-making with regard to medical treatment and intervention.
  • MPI is used for the assessment and comparison of left ventricular function during both post-stress and rest conditions, and is done in conjunction with cardiac stress test.
  • the radioimaging is for use in the prognosis and risk stratification of a cardiac disease in patients with known or suspected cardiovascular or cardiac disease or disorder as described herein (e.g., CAD).
  • the radioimaging is for use in the prediction of functional recovery following acute myocardial infarction.
  • the radioimaging is for use in in the prediction of functional recovery after revascularization in patients with chronic ischemic left ventricle (LV) dysfunction.
  • an additional noninvasive imaging modality e.g. stress echocardiography; radioimaging with other agents; other imaging methods
  • radioimaging e.g. stress echocardiography; radioimaging with other agents; other imaging methods
  • the radioimaging (e.g., MPI) is for determining a blood flow to the heart muscle, for determining the effects of a heart attack, or myocardial infarction, on areas of the heart, for identifying areas of the heart muscle that would benefit from a procedure such as angioplasty or coronary artery bypass surgery (in combination with a myocardial perfusion scan) or for mapping a normal heart function.
  • the patient suffers from, or has predisposition to suffer from, or has symptoms which may be associated with, a disease or disorder as described herein (e.g., a cardiac or cardiovascular disease or disorder as described herein).
  • a disease or disorder as described herein e.g., a cardiac or cardiovascular disease or disorder as described herein.
  • the radioimaging is performed following subjecting the patient to a therapy of the disease or disorder (associated with impaired structure and/or or function of OCT-expressing cell, tissue or organ), and is for monitoring the patient's responsiveness to the therapy and/or for monitoring the efficacy of the therapy.
  • a therapy of the disease or disorder associated with impaired structure and/or or function of OCT-expressing cell, tissue or organ
  • the method is effected by:
  • the method is effected by:
  • a severity of the disease or disorder e.g., an extent of impaired structure and/or function of the cell, tissue or organ
  • the imaging parameter is compared with a control reference that correlates with the severity of the disease or disorder, wherein the comparison allows for determining of the severity of the disease or disorder in the subject.
  • the method further comprises monitoring the efficacy of the therapy, following a first time period of the therapy, by: Subjecting the patient to a second radioimaging (which is preferably the same as the first radioimaging), to thereby determine the same imaging parameter of the OCT-expressing cell, tissue or organ;
  • a severity of the disease or disorder e.g., an extent of impaired structure and/or function of the cell, tissue or organ
  • the imaging parameter is compared with the imaging parameter obtained in the first radioimaging, wherein the comparison allows determining the efficacy of the therapy.
  • the therapy can comprise a drug therapy, or an intervening therapy (e.g., surgery, angioplasty, etc.).
  • imaging parameter refers to any parameter which can be measured using the radioimaging, including, but are not limited to, images (e.g. four-dimensional images or pictures of functional processes in the body) acquired by the radioimaging.
  • the radioimaging is MPI
  • the imaging parameter includes, for example, one or more of images which correlate with myocardial vascular resistance, the extent of blood supply to the heart muscle (e.g. pointing to inadequate blood supply in specific regions of the heart), information about the heart's pumping function, the amount of scarring from a heart attack, the success of coronary bypass surgery or angioplasty.
  • the imaging parameter is a presence and/or level and/or distribution and/or distribution rate of the radiolabeled compound in the patient's body or a part thereof.
  • the radioimaging further comprises, prior to administering the radiolabeled compound to a patient, preparing the radiolabeled compound.
  • the radiolabeled compound is prepared as described herein in any of the respective embodiments and any combination thereof.
  • the radiolabeled compound is prepared 1, 2, 3 or even more hours before being administered to the patient, depending on the radioactive atom used (and its half life).
  • any of the radiolabeled compounds described herein can be formulated into a pharmaceutical composition which can be used for radiotherapy of a disease or for imaging, as described herein in any of the methods and uses and respective embodiments thereof.
  • a composition includes as an active ingredient any of the radiolabeled compounds described herein and a pharmaceutically acceptable carrier.
  • a "pharmaceutical composition” refers to a preparation of one or more of the radiolabeled compounds described herein, with other chemical components such as pharmaceutically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • examples, without limitations, of carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Suitable routes of administration may, for example, include intravenous, intraperitoneal, intranasal, or intraocular injections, oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intracardiac, e.g., into the right or left ventricular cavity, or into the common coronary artery.
  • tissue refers to part of an organism consisting of cells designed to perform a function or functions. Examples include, but are not limited to, pulmonary tissue, pancreatic tissue, brain tissue, retina, skin tissue, hepatic tissue, breast tissue, bone, cartilage, connective tissue, blood tissue, muscle tissue, cardiac tissue, vascular tissue, renal tissue, gonadal tissue, rectal tissue, and hematopoietic tissue.
  • compositions of some embodiments of the invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with some embodiments of the invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to some embodiments of the invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the active compound and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • compositions of some embodiments of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • a pharmaceutical composition as described herein is prepared prior to administration to a patient.
  • a pharmaceutical composition as described herein comprises a fluorine- 18 radiolabeled compound as described herein, and is prepared 20-240 minutes, or 30 to 240 minutes, or 30 to 180 minutes, or 30 to 120 minutes, or 30 to 60 minutes, prior to administration to a patient.
  • a pharmaceutical composition as described herein comprises a bromine-76 or bromine-77 radiolabeled compound as described herein, and can be prepared 1-48 hours, or 1-24 hours minutes, prior to administration to a patient, although shorter time periods are also contemplated.
  • a pharmaceutical composition as described herein comprises iodine- 123, iodine- 124 or iodine- 131 radiolabeled compound as described herein, and can be prepared from 1 hour to several days, prior to administration to a patient, as described herein, although shorter time periods are also contemplated.
  • a radioimaging method as described herein is performed 0-120 minutes, or 0-60 minutes, or 0-40 minutes, or 0-20 minutes, after administration of the composition to a patient.
  • radioactive atom and respective nuclear imaging techniques
  • the compounds described herein, including the radiolabeled compounds, include quaternary ammonium salts, and in some of any of the embodiments described herein, these salts are pharmaceutically acceptable salts.
  • the present embodiments encompass any enantiomers, diastereomers, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of the compounds described herein.
  • enantiomer refers to a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other. Enantiomers are said to have "handedness” since they refer to each other like the right and left hand. Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems.
  • a compound may exhibit one or more chiral centers, each of which exhibiting an R- or an 5-configuration and any combination, and compounds according to some embodiments of the present invention, can have any their chiral centers exhibit an R- or an 5-configuration.
  • diastereomers refers to stereoisomers that are not enantiomers to one another. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter they are epimers. Each stereo-center (chiral center) gives rise to two different configurations and thus to two different stereoisomers.
  • embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of stereo-configuration, namely any diastereomer.
  • prodrug refers to an agent, which is converted into the active compound (the active parent drug) in vivo.
  • Prodrugs are typically useful for facilitating the administration of the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • a prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions.
  • Prodrugs are also often used to achieve a sustained release of the active compound in vivo.
  • An example, without limitation, of a prodrug would be a compound of the present invention, having one or more carboxylic acid moieties, which is administered as an ester (the "prodrug").
  • Such a prodrug is hydrolyzed in vivo, to thereby provide the free compound (the parent drug).
  • the selected ester may affect both the solubility characteristics and the hydrolysis rate of the prodrug.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the compound of the present invention) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.
  • Suitable solvents include, for example, ethanol, acetic acid and the like.
  • hydrate refers to a solvate, as defined hereinabove, where the solvent is water.
  • hydroxyl or "hydroxy”, as used herein, refer to an -OH group.
  • amine describes a -NR'R" group where each of R' and R" is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, alkaryl, alkheteroaryl, or acyl, as these terms are defined herein.
  • R' and R" can be, for example, hydroxy, alkoxy, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carbonyl, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • amide also describes a -NR.'- linking group (a biradical group, attached to two moieties), with R' as described herein.
  • alkyl describes an aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl may have 1 to 20 carbon atoms, or 1-10 carbon atoms, and may be branched or unbranched. Whenever a numerical range; e.g., "1-10", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkyl is a lower alkyl, including 1-6 or 1-4 carbon atoms.
  • an alkyl can be substituted or unsubstituted.
  • the substituent can be, for example, one or more of an alkyl (forming a branched alkyl), an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heteroalicyclic, a halo, a trihaloalkyl, a hydroxy, an alkoxy and a hydroxyalkyl as these terms are defined hereinbelow.
  • An alkyl substituted by aryl is also referred to herein as "alkaryl", an example of which is benzyl.
  • the alkyl can be substituted by other substituents, as described hereinbelow.
  • alkenyl describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond, e.g., allyl, vinyl, 3-butenyl, 2-butenyl, 2-hexenyl and i-propenyl.
  • the alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.
  • alkynyl is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.
  • cycloalkyl refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms), branched or unbranched group containing 3 or more carbon atoms where one or more of the rings does not have a completely conjugated pi-electron system, and may further be substituted or unsubstituted.
  • exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclododecyl.
  • the cycloalkyl can be substituted or unsubstituted.
  • aryl describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • the aryl group may be unsubstituted or substituted by one or more substituents.
  • An aryl substituted by alkyl is also referred to herein as "aralkyl", as example of which is toluyl.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine and the like.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents.
  • heteroalicyclic describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi- electron system. Representative examples are morpholine, piperidine, piperazine, tetrahydrofurane, tetrahydropyrane and the like.
  • the heteroalicyclic may be substituted or unsubstituted.
  • halide refers to the anion of a halo atom, i.e. F " , CI " , Br “ and ⁇ .
  • halo or halogen refers to F, CI, Br and I atoms as substituents.
  • alkoxide refers to an R'-O " anion, wherein R' is as defined hereinabove.
  • alkoxy refers to an -OR' group, wherein R' is alkyl or cycloalkyl, as defined herein.
  • aryloxy refers to an -OR' group, wherein R' is aryl, as defined herein.
  • heteroaryl oxy refers to an -OR' group, wherein R' is heteroaryl, as defined herein.
  • thioalkoxy refers to an -SR' group, wherein R' is alkyl or cycloalkyl, as defined herein.
  • thioaryloxy refers to an -SR' group, wherein R' is aryl, as defined herein.
  • thioheteroaryloxy refers to an -SR' group, wherein R' is heteroaryl, as defined herein.
  • hydroxyalkyl refers to an alkyl group, as defined herein, substituted with one or more hydroxy group(s), e.g., hydroxymethyl, 2-hydroxyethyl and 4- hydroxypentyl.
  • aminoalkyl refers to an alkyl group, as defined herein, substituted with one or more amino group(s).
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy group(s), e.g., methoxymethyl, 2-methoxyethyl, 4-ethoxybutyl, n-propoxyethyl and t-butylethyl.
  • trihaloalkyl refers to -CX 3 , wherein X is halo, as defined herein.
  • An exemplary haloalkyl is CF 3 .
  • alkyl, cycloalkyl, aryl, alkaryl, heteroaryl, heteroalicyclic, acyl and any other moiety or group as described herein includes one or more substituents, each can independently be, but are not limited to, hydroxy, alkoxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, alkaryl, alkyl, alkenyl, alkynyl, sulfonate, sulfoxide, thiosulfate, sulfate, sulfite, thiosulfite, phosphonate, cyano, nitro, azo, sulfonamide, carbonyl, thiocarbonyl, C- carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, oxo, thiooxo, oxime, acyl, acyl halide, azo, azide,
  • cyano describes a -C ⁇ N group.
  • nitro describes an -N0 2 group.
  • carboxylate as used herein encompasses C-carboxylate and O-carboxylate.
  • a carboxylate can be linear or cyclic.
  • R' and the carbon atom are linked together to form a ring, in C-carboxylate, and this group is also referred to as lactone.
  • R' and O are linked together to form a ring in O-carboxylate.
  • Cyclic carboxylates can function as a linking group, for example, when an atom in the formed ring is linked to another group.
  • thiocarboxylate as used herein encompasses C-thiocarboxylate and O- thiocarboxylate.
  • a thiocarboxylate can be linear or cyclic.
  • R' and the carbon atom are linked together to form a ring, in C-thiocarboxylate, and this group is also referred to as thiolactone.
  • R' and O are linked together to form a ring in O-thiocarboxylate.
  • Cyclic thiocarboxylates can function as a linking group, for example, when an atom in the formed ring is linked to another group.
  • carboxylate as used herein encompasses N-carbamate and O-carbamate.
  • a carbamate can be linear or cyclic.
  • R' and the carbon atom are linked together to form a ring, in O-carbamate.
  • R' and O are linked together to form a ring in N-carbamate.
  • Cyclic carbamates can function as a linking group, for example, when an atom in the formed ring is linked to another group.
  • carboxylate as used herein encompasses N-carbamate and O-carbamate.
  • thiocarbamate encompasses N-thiocarbamate and O- thiocarbamate.
  • Thiocarbamates can be linear or cyclic, as described herein for carbamates.
  • dithiocarbamate encompasses S-dithiocarbamate and N- dithioc arb amate .
  • amide as used herein encompasses C-amide and N-amide.
  • hydrozine describes a -NR'-NR"R" ' end group or a -NR'-NR"- linking group, as these phrases are defined hereinabove, with R', R", and R" as defined herein.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • 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 subranges 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 subranges 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, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • subject describes animals, including mammals, preferably human beings, at any age, which suffer, or are at risk to suffer, or are suspected as suffering, from a pathology. Preferably, this term encompasses individuals who are at risk to develop the pathology.
  • tissue refers to part of an organism consisting of cells designed to perform a function or functions. Examples include, but are not limited to, brain tissue, retina, skin tissue, hepatic tissue, pancreatic tissue, bone, cartilage, connective tissue, blood tissue, muscle tissue, cardiac tissue, vascular tissue, renal tissue, pulmonary tissue, gonadal tissue, hematopoietic tissue, and tumor tissue, including benign and malignant tumor tissues.
  • Radioactive halides are generated as follows:
  • Radioactive fluoride- 18 ion is produced via the 180(p,n) 18 F nuclear reaction using a IB A cyclotron equipped with a fluorine- 18 target.
  • the [ 18 F]fluoride is delivered from the cyclotron
  • [ 18 F]Fluoride is then eluted into the reaction vessel using aqueous potassium carbonate (4 mg in 0.5 mL of water).
  • Radioactive iodine- 123, radioactive iodine- 124 and radioactive iodine- 131 are obtainable from commercial vendors.
  • Radioactive bromine-76 and radioactive bromine-77 are obtainable from commercial vendors.
  • Radiochemical purity is determined using an analytical HPLC Varian ProStar model 230 (Palo Alto, CA, USA) equipped with UV Detector, JASCO UV-2075 plus (Tokyo, Japan) and PMT/scintillator detector Bioscan flow count).
  • Preparative HPLC is performed using a Varian 9012Q HPLC system employed with an Varian 9050 UV-VIS detector and C18 HPLC column (Bischoff Nucleosil CI 8, 7 ⁇ , 250 mm x 16 mm, Marchery-Nagel GmbH, Duren, Germany).
  • Varian 9012Q HPLC system employed with a Varian 9050 UV-VIS detector and C18 column (Luna, Phenomenex, Torrance, CA, USA).
  • Analytical HPLC is performed using analytical HPLC Varian ProStar model 230 (Palo Alto, CA, USA) equipped with UV Detector, JASCO UV-2075 plus (Tokyo, Japan). 1H-NMR and 19 F-NMR spectra are obtained using Varian VXR-300 (300 MHz spectrometer equipped with a 5 mm probe).
  • HRMS was performed using an ESI LTQ Orbitrap XL spectrophotometer equipped with FTMS Analyzer (Resolution: 100000). The data collected using Xcalibur 2.1 program.
  • 2-Fluoroethanol 120 mg, 1.87 mmol, Sigma Aldrich was dissolved in dry dichloromethane (2 mL) and added to a solution of /?-toluenesulfonyl chloride (540 mg, 2.83 mmol, Sigma Aldrich), 252mg of trimethylamine (4.26 mmol, Sigma Aldrich) and 26 mg (212.8 ⁇ , Sigma Aldrich) DMAP dissolved in 2 mL dry dichloromethane. The reaction was stirred for 2 hours at room temperature and was thereafter concentrated and purified on a silica gel column using hexane:ethyl acetate (9:1) as eluent to yield the fluoroethyl tosylate.
  • the crude product was purified using a semi- preparative HPLC system equipped with a semi-preparative column (Luna C I 8, 100 A, 5 ⁇ , 250x10 mm) using (A) H 2 0: (B) acetonitrile gradient (from 100% to 60% (A) over 15 minutes at a constant gradient and flow, 4 mL/minute).
  • Fluorine- 18 labeled FEtQ was prepared in a one-step radiosynthesis using 2-N'- ethylquinolinium triflate.
  • 2-N'-ethylquinolinium triflate was prepared by a two-step reaction, as depicted in Scheme 2 below.
  • the first step involved synthesis of the reagent ethylene glycol bistriflate, which was further reacted with quinoline in the second step, to yield 2-N'- ethylquinolinium triflate.
  • the latter was analyzed by 1H, 19 F and 13 C NMR, high resolution mass spectrometry (HR-MS) and by HPLC.
  • [ F]FEtQ was synthesized using an automated GE TRAER Lab module. Reagent vials were loaded as follows: Vial 1: potassium carbonate (0.5 mL of a 8 mg/mL solution, Sigma Aldrich), Vial 2: kryptofix-2.2.2 (15 mg dissolved in 1 mL MeCN, Merck, Darmstadt, Germany), Vial 3: ethyltriflatequinoline 17-20 mg dissolved in 1.4 mL dry dichloromethane, Vial 4: 1.9 mL of HPLC eluent (97:3 of acetate buffer 0.1 M, pH 5.2: EtOH), Collection vial: 0.9% sodium chloride solution for injection (5 mL).
  • the radioactive fluoride- 18 anion was produced via the 18 ⁇ ( ⁇ , ⁇ ) 18 F nuclear reaction using an IBA cyclotron equipped with a target for generating [ 18 F]fluoride.
  • the latter was delivered from the cyclotron (in a 3 mL bolus of [ 180]H 2 0), and trapped on a solid phase extraction anion exchange cartridge (CHROMAFIX PS-HCO 3 , Marcherey Nagle, Diiren,
  • the obtained mixture was filtered through a polypropylene 0.45 ⁇ filter (Whatman, GE Healthcare) and further purified on a semi-preparative HPLC system using RP-C18 column (Luna, Phenomenex) using 97 % acetate buffer pH 5.2, 0.1 M and 3 % of ethanol in a constant ratio (isocratic) eluent at a flow of 4 mL/ min.
  • [ 18 F]FEtQ retention time was 18.5 minutes and a peak of 30-45 sec (2-3 mL) was transferred to the collection vial containing 5 mL of saline.
  • a Phenomenex Luna CI 8(2) column (5 ⁇ , 100A, 4.6 mm x 250 mm) was used, with a gradient mobile phase system of (A) 0.05% TFA in water: (C) 0.05 % TFA in acetonitrile at a constant flow rate of 1.2 mL/min (gradient from 100 % to 65 % (A) in 22 minutes).
  • Residual kryptofix-2.2.2 (K222) levels in the final product were analyzed using the established spot test. Strips of plastic coated with silica gel, TLC plates saturated with iodoplatinate reagent were spotted with standard solutions containing 0, 0.025, 0.05 and 0.01 mg/mL of kryptofix 2.2.2, dissolved in 97 % of 0.1 M acetate buffer (pH 5.2) and 3 % of EtOH. The absence of kryptofix 2.2.2 in the final product was confirmed or appeared lower than 0.025 mg/mL.
  • Solvent residues were analyzed using a 1 injection of the final product to a GC instrument, and compared to a standard solution containing 0.04 % acetonitrile and 0.5 % acetone. Standard area counts and corresponding retention times were 23,172 area counts at 6.4 minutes for acetonitrile, and 275,328 area counts at 8.9 minutes, for acetone.
  • the solution was inspected for its clearness and transparency and was colorless or in some cases light yellow.
  • HEK293 cells were stably transfected with the cDNAs of hOCTl, hOCT2, hOCT3 or the empty (pcDNA3) vector (EV) and were obtained from Prof. Griindemann, Department of Pharmacology, University Hospital Cologne, Germany [Gêtmann, D., et al., Biol Chem, 1997; 272(16): 10408-13].
  • the cells were cultured at 37 °C in an atmosphere of 5 % C0 2 and 95 % relative humidity, in DMEM (lg/L glucose) with 10 % FBS and penicillin- streptomycin (lOOU/0.1 mg/ mL). Expression of the hOCTl -2 or -3 was verified by RT-PCR.
  • Corticosterone is an inhibitor of the hOCTl-3, with about 100-fold higher potency for hOCT3 compared to hOCTl and hOCT2 [Koepsell et al. Pharm Res. Jul 2007 ;24(7): 1227- 1251]. In vitro uptake inhibition experiments were therefore conducted in the presence of corticosterone, to test hOCT3 uptake inhibition.
  • HEK293 cells stably expressing the hOCT3 or EV were incubated in Krebs-Ringer- Henseleit buffer (pH 7.4) and pretreated for 30 minutes with various concentrations of corticosterone (0.05, 0.5 and 5.0 ⁇ ), before a 15 minutes co-incubation with [ 18 F]FEtQ.
  • TACs time-activity curves
  • FIGs. 4A-D show that [ 18 F]FEtQ yielded good quality images, with clear visualization of the LV and good contrast between the heart and its surrounding tissues.
  • the distribution of radioactivity at 45 minutes after injection of [ 18 F]FEtQ was also studied by sacrificing each rat following its PET acquisition, harvesting organs and tissues of interest and measuring their radioactivity concentration.
  • the major route of elimination was via renal clearance (see also FIG. 3B). Except for the urinary bladder, the highest radioactivity levels were measured in the heart, followed by the kidneys and the liver.
  • corticosterone i.v. (3.3 mg/ kg) or vehicle 5 minutes prior to the i.v. injection of [ F]FEtQ (16.5 + 2 MBq).
  • blood samples were drawn approximately 3 minutes after corticosterone or vehicle injection, and analyzed for corticosterone levels in serum.
  • FIGs. 5A-C present time-activity curves of the LV (FIG. 5A), liver (FIG. 5B) and
  • [ F]FEtQ could be inhibited by corticosterone.
  • Serum-corticosterone levels in blood samples taken from animals at 3 minutes after corticosterone injection were 6.33 + 1.66 ⁇ (mean + SEM) (compared to 0.55 + 0.16 ⁇ (mean + SEM) in vehicle-treated rats). These levels are in good agreement with the reported IC 50 values of corticosterone for OCT2 and 3 (4-5 ⁇ ; Koepsell et al. 2007 (supra)).
  • OCT2 and 3 4-5 ⁇ ; Koepsell et al. 2007 (supra)
  • the compound (94.35 MBq) was injected into an anesthetized female macaque monkey, weighing 4.7 Kg.
  • the PET acquisition was composed of a 15-minutes dynamic scan, focused over the thorax, followed by three whole-body scans of 9 minutes each.
  • the obtained images are presented in FIG. 6 and show that the major routes of elimination were renal and hepatobiliary, resulting in an intense radioactive signal in both the intestines and the urinary bladder.
  • mice Human OCT2 expressing tumor-bearing mice were established by subcutaneous injection of hOCT2 overexpressing HEK293 cells, into athymic nude mice. After tumor development, mice were anesthetized with isoflurane (1.5-2.5 % in 0 2 ) and subjected to a CT attenuation- correction scan. Subsequent 1-hour dynamic PET acquisitions were started at the time of i.v.
  • the affinity (Km) of [ 18 F]FEtQ to human OCT 1-3 is determined according to the following study protocol.
  • Affinity tests for [ 18 F]FEtQ experiments are performed using HEK293 cells expressing human OCT 1/2/3 or empty vector.
  • the solution is sterilized by filtration or autoclaving. The solution is stable for 2-4 months in a refrigerator.
  • Wells are coated with Poly-L-ornithine (0.6 mL solution as described hereinabove was placed in each well, wells were incubated for at least 20 minutes at room temperature on an orbital shaker, the solution was thereafter aspirated and the wells were washed with 1.0 mL medium without FCS, which was thereafter aspirated). Prior to cells seeding, 2 mL growth medium is added to each well.
  • Poly-L-ornithine 0.6 mL solution as described hereinabove was placed in each well, wells were incubated for at least 20 minutes at room temperature on an orbital shaker, the solution was thereafter aspirated and the wells were washed with 1.0 mL medium without FCS, which was thereafter aspirated). Prior to cells seeding, 2 mL growth medium is added to each well.
  • the tested HEK293 cells are suspended in the growth medium and their concentration is determined using a haemocytometer.
  • the medium is then replaced by a pre -heated (20 °C) transfer buffer (KHR solution), and the wells are incubated for 20 minutes at room temperature.
  • KHR solution a pre -heated (20 °C) transfer buffer
  • Krebs-Pvinger-Henseleit (KRH) solution Transfer buffer; TB
  • KRH Krebs-Pvinger-Henseleit
  • [ 18 F]FEtQ is added to all plates (0.250 mL/well) using 12 mL Combitips and the wells are incubated for various time periods at room temperature. At a relevant time point, the medium is rapidly aspirated from the wells, wells are washed twice with ice-cold PBS (4 mL/well), the PBS is aspirated, and 0.5 mL 1 % triton is added. The cells in each well are thereafter scraped, transferred to marked Eppendorf tubes and triturated to ensure complete lysis. 300 ⁇ ⁇ of each cell lysate is thereafter transferred into a marked tube/vial for gamma counter readings.
  • the remaining lysate is kept at 4 °C overnight or at -20 °C for longer periods of time, for protein estimations after the radioactivity has decayed, using the Novagen BCA protein Assay Kit.
  • [ 18 F]FEtQ calibration curve is prepared by inserting 0.3 mL of PBS in each tube, adding approximately 24 ⁇ /0.6 mL (directly from the stock solution) into a marked tube, and transferring 0.3 mL in 15 serial dilutions. The samples are then placed in the gamma counter and count twice.
  • Measurements of the Total Activity in the wells is performed by directly transfering 20 ⁇ L ⁇ (into 0.3 mL PBS) from a stock solution into the respective gamma counter tubes. Measurements are performed in triplicates.
  • Radiosynthesis was carried out on an automated module (GE, Munster Germany).
  • C- carbon dioxide was produced by the 14 N(p,a) u C nuclear reaction on nitrogen containing 0.5 % oxygen, using an 18/9 IB A cyclotron.
  • the target gas was delivered and trapped by a cryogenic trap in the [ u C]CH 3 l module.
  • Carbon- 11 Mel was prepared as follows: [ u C]C0 2 (44 GBq, 1,000 mCi) was trapped at - 160 °C. The temperature of the cooling trap was increased to -20 °C, and the activity was transferred by a stream of argon (40 mL/minute) into the first reactor containing 300 ⁇ ⁇ of 0.25 N LiAlH 4 in THF at -50 °C. After 90 seconds, the solvent was removed under reduced pressure. In this manner, approximately 66 % of the activity was recovered.
  • the reactor temperature was increased to 160 °C, HI (Hydroiodic acid, 57 %) was added and the obtained [ n C]MeI was distilled (argon flow of 15 mL/minute) through a NaOH column to the second reactor, containing quinoline 32.8 mg (0.23 mmol) dissolved in 400 ⁇ ⁇ of acetonitrile at -20 °C.
  • the reactor was sealed and heated to 80 °C for seven minutes and then the solvent was removed under argon flow, at 75 °C.
  • the mixture was cooled to 40 °C, followed by the addition of 2 mL of ethanol/water (1: 1), and the crude product was transferred into an SPE flask containing 5 mL of water.
  • TACs time-activity curves

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des composés de sel d'ammonium quaternaire radiomarqués présentant un squelette de quinoléine et leurs utilisations en radioimagerie. Les composés radiomarqués peuvent être utilisés pour déterminer la présence et/ou le niveau et/ou la distribution d'un transporteur de cations organiques dans un corps d'un patient et pour déterminer si le patient présente une maladie ou un trouble qui peut être traité par, ou en réponse à une thérapie dont l'efficacité est en corrélation avec la présence et/ou le niveau d'un transporteur de cations organiques. L'invention concerne également l'utilisation de ces composés radiomarqués dans le traitement d'une telle maladie ou d'un tel trouble. Les composés radiomarqués de la présente invention peuvent également être utilisés dans l'imagerie des cellules, des tissus et/ou des organes exprimant OCT, pour déterminer la présence et/ou le niveau d'une structure ou d'une fonction altérée de cellules, de tissus et/ou d'organes exprimant OCT, et/ou d'une maladie ou d'un trouble associé à une telle structure et/ou d'une telle fonction altérée.
PCT/IL2018/050517 2017-05-11 2018-05-11 Composés radiomarqués ciblant des transporteurs de cations organiques et leurs utilisations en radioimagerie WO2018207193A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762504618P 2017-05-11 2017-05-11
US62/504,618 2017-05-11

Publications (1)

Publication Number Publication Date
WO2018207193A1 true WO2018207193A1 (fr) 2018-11-15

Family

ID=64104696

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2018/050517 WO2018207193A1 (fr) 2017-05-11 2018-05-11 Composés radiomarqués ciblant des transporteurs de cations organiques et leurs utilisations en radioimagerie

Country Status (1)

Country Link
WO (1) WO2018207193A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020050729A1 (fr) * 2018-09-05 2020-03-12 Synektik S.A. Composé radiomarqué de sel d'ammonium quaternaire d'une amine aromatique polycyclique, utilisation du composé radiomarqué dans un procédé de diagnostic de tomographie par émission de positrons, et composition pharmaceutique contenant le composé radiomarqué de sel d'ammonium quaternaire d'une amine aromatique polycyclique
CN111349027A (zh) * 2018-12-21 2020-06-30 石家庄圣泰化工有限公司 1,2-双［（三氟代甲基）磺酰基氧基］乙烷的合成方法
CN113597310A (zh) * 2019-03-15 2021-11-02 普瑞尼亚神经治疗有限公司 使用普利多匹定治疗线粒体相关疾病和病症，包含其症状

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2320647C1 (ru) * 2006-12-20 2008-03-27 Естественнонаучный институт государственного образовательного учреждения высшего профессионального образования "Пермский государственный университет" Меченные тритием n-фенилхинолиниевые и хинальдиниевые соли и способ их получения
WO2010141833A2 (fr) * 2009-06-05 2010-12-09 The General Hospital Corporation Conjugués de fluorochrome vitaux et procédés d'utilisation
RU2442776C1 (ru) * 2010-09-21 2012-02-20 Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" Меченные тритием n-фениллепидиниевые соли и способ их получения

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2320647C1 (ru) * 2006-12-20 2008-03-27 Естественнонаучный институт государственного образовательного учреждения высшего профессионального образования "Пермский государственный университет" Меченные тритием n-фенилхинолиниевые и хинальдиниевые соли и способ их получения
WO2010141833A2 (fr) * 2009-06-05 2010-12-09 The General Hospital Corporation Conjugués de fluorochrome vitaux et procédés d'utilisation
RU2442776C1 (ru) * 2010-09-21 2012-02-20 Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" Меченные тритием n-фениллепидиниевые соли и способ их получения

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
AMETAMEY, S. M. ET AL.: "Molecular imaging with PET", CHEMICAL REVIEWS, vol. 108, no. 5, 22 April 2008 (2008-04-22), pages 1501 - 1516, XP002724498, Retrieved from the Internet <URL:https://s3.amazonaws.com/academia.edu.documents/42643495/Molecular_imaging_with_PET20160213-23763-1c9gcnp.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1533655374&Signature=O2xQVTsJGokQbtnVjl%2FgMmtcMl8%3D&response-content-disposition=inline%3B%20filename%3DMolecular_Imaging_with_PET.pdf> *
BOHN, P. ET AL.: "Dihydroquinoline carbamate derivatives as ''bio-oxidizable'' prodrugs for brain delivery of acetylcholinesterase inhibitors: [11C] radiosynthesis and biological evaluation", ACS CHEMICAL NEUROSCIENCE, vol. 6, no. 5, 19 February 2015 (2015-02-19), pages 737 - 744, XP055557193, Retrieved from the Internet <URL:https://s3.amazonaws.com/academia.edu.documents/39421987/cn5003539.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1533467071&Signature=1xMvUa2YX7ZkzyqYwX83oiRVEAk%3D&response-content-disposition=inline%3B%20filename%3DDihydroquinoline_Carbamate_Derivatives_a.pdf> *
CHEMICAL ABSTRACTS, 24 January 2001, Columbus, Ohio, US; abstract no. 316366-02-6, "CA Index Name: Quinolinium, 4-amino-1-(decyl-5,6- t2)-2-methyl-, iodide" *
FOUCOUT, L. ET AL.: "Synthesis, radiosynthesis and biological evaluation of 1, 4-dihydroquinoline derivatives as new carriers for specific brain delivery", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 7, no. 18, 10 July 2009 (2009-07-10), pages 3666 - 3673, XP055557192, Retrieved from the Internet <URL:http://222.252.30.203:8888/bitstream/123456789/13207/l/3666.pdf> *
GOURAND, F. ET AL.: "Chemical delivery system of metaiodobenzylguanidine (MIBG) to the central nervous system", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 3, 19 January 2010 (2010-01-19), pages 1281 - 1287, XP055557185, Retrieved from the Internet <URL:http://booksc.org/book/29863587/c40bb0> *
OKAMURA, T. ET AL.: "A 1 IC-labeled 1, 4-dihydroquinoline derivative as a potential PET tracer for imaging of redox status in mouse brain", JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM, vol. 35, no. 12, 17 June 2015 (2015-06-17), pages 1930 - 1936, XP055557197, Retrieved from the Internet <URL:http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2015.132> *
SUHRE, W. M. ET AL.: "Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters, hOCT2 and rbOCT2", MOLECULAR PHARMACOLOGY, vol. 67, no. 4, 1 April 2005 (2005-04-01), pages 1067 - 1077, XP055557201, Retrieved from the Internet <URL:http://molpharm.aspetjournals.org/content/67/4/1067.1ong> *
WANG, M. ET AL.: "Simple synthesis of carbon-11 labeled styryl dyes as new potential PET RNA- specific, living cell imaging probes", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 5, 7 March 2009 (2009-03-07), pages 2300 - 2306, XP026029643, Retrieved from the Internet <URL:http://booksc.org/book/3529403/759eb2> *
ZHUO, S. ET AL.: "Photo inactivation of the bovine heart mitochondrial Fl-ATPase by [14C] dequalinium crosslinks phenylalanine-403 or phenylalanine-406 of an alpha subunit to a site or sites contained within residues 440-459 of a beta subuni t", BIOCHEMISTRY, vol. 32, no. 9, 9 March 1993 (1993-03-09), pages 2219 - 2227, Retrieved from the Internet <URL:http://booksc.org/book/29550784/2c4f46> *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020050729A1 (fr) * 2018-09-05 2020-03-12 Synektik S.A. Composé radiomarqué de sel d'ammonium quaternaire d'une amine aromatique polycyclique, utilisation du composé radiomarqué dans un procédé de diagnostic de tomographie par émission de positrons, et composition pharmaceutique contenant le composé radiomarqué de sel d'ammonium quaternaire d'une amine aromatique polycyclique
CN111349027A (zh) * 2018-12-21 2020-06-30 石家庄圣泰化工有限公司 1,2-双［（三氟代甲基）磺酰基氧基］乙烷的合成方法
CN113597310A (zh) * 2019-03-15 2021-11-02 普瑞尼亚神经治疗有限公司 使用普利多匹定治疗线粒体相关疾病和病症，包含其症状

Similar Documents

Publication Publication Date Title
US9701678B2 (en) Small-molecule HSP90 inhibitors
Kurihara et al. Radiolabelled agents for PET imaging of tumor hypoxia
CN116617420A (zh) 靶向成纤维细胞活化蛋白α的化合物、药物组合物及用途
WO2018207193A1 (fr) Composés radiomarqués ciblant des transporteurs de cations organiques et leurs utilisations en radioimagerie
Slobbe et al. A comparative PET imaging study with the reversible and irreversible EGFR tyrosine kinase inhibitors [11 C] erlotinib and [18 F] afatinib in lung cancer-bearing mice
US8568693B2 (en) Therapy selection method
KR101879431B1 (ko) 황화수소 검출용 방사성 프로브
HU230375B1 (hu) Tioflavin-származékok és alkalmazásuk az Alzheimer-kór diagnózisában és kezelésében
Rizvi et al. Synthesis of 99mTc-labeled 2-Mercaptobenzimidazole as a novel radiotracer to diagnose tumor hypoxia
Hou et al. Development of candidates for positron emission tomography (PET) imaging of ghrelin receptor in disease: design, synthesis, and evaluation of fluorine-bearing quinazolinone derivatives
AU2015326506B2 (en) Novel anthranilic acid derivatives
ES2907130T3 (es) Darapladib radiomarcado, análogos del mismo y su uso como compuestos para la obtención de imágenes
Beirne et al. Metal-tyrosine kinase inhibitors: targeted metal-drug conjugates
ES2833959T3 (es) Inhibidor del EGFR macrocíclico radiomarcado
Echigo et al. Development and evaluation of a theranostic probe with RGD peptide introduced platinum complex to enable tumor-specific accumulation
US20060239915A1 (en) Labeled macrophage scavenger receptor antagonists for imaging cardiovascular diseases
US20170096434A1 (en) Derivatized corroles and metallocorroles and their use as imaging and therapeutic agents
Sivapackiam et al. Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport
US10710968B2 (en) Radiolabeled erlotinib analogs and uses thereof
US11884685B2 (en) Rhenium complexes and methods of use for treating cancer
EP3111960B1 (fr) Agent d&#39;imagerie de diagnostic de médecine nucléaire
Makino et al. Development of novel PET probes targeting phosphatidylinositol 3-kinase (PI3K) in tumors
JP6999331B2 (ja) 新規糖尿病治療剤
US20220347323A1 (en) Positron Emission Tomography Guided Delivery of Mitochondral Complex I Inhibitors
Montagner et al. Metal-Tyrosine Kinase Inhibitors: Targeted Metal-drug Conjugates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18798847

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18798847

Country of ref document: EP

Kind code of ref document: A1