Imaging agents and methods of imaging naaladase or psma

Abstract

The present invention relates to compounds particularly asymmetric urea compounds which are labeled with one or more radioisotopes and which are suitable for imaging or therapeutic treatment of tissues, organs, or tumors which express NAALADase and/or PSMA. In another embodiment, the invention relates to methods of imaging tissues, organs, or tumors using radiolabeled compounds of the invention, particularly tissues, organs, or tumors which express NAALADase and/or PSMA to which the compounds of the invention have an affinity.

1 . A compound according to Formula I 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of fluoroalkyl, aryl, benzyl, thiol, and alkylthiol, each of which is optionally substituted with an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkanoyl, or optionally substituted aralky, optionally substituted alkoxy, optionally substituted aralkyloxy, or optionally substituted phenoxy; 
         Q is hydrogen, optionally substituted alkyl, optionally substituted benzyl or optionally substituted phenyl; and 
         Z is Q or a tetrazole; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein the R group comprises at least one radioactive isotope or fluorescent dye. 
     
     
         3 . The compound of  claim 1 , wherein the R group comprises one or more positron emitting radioactive isotopes. 
     
     
         4 . The compound of  claim 1 , wherein the R group comprises one or more isotopes selected from  11 C,  18 F,  99 Tc,  123 I or any combination thereof. 
     
     
         5 . The compound of  claim 1 , wherein the compound is according to Formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound is according to Formula II 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted fluoroalkyl, optionally substituted aryl, optionally substituted aralkyl; or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound of  claim 6 , wherein R 1  comprises one or more fluorescent dyes, radioisotopes selected from  11 C,  18 F,  99 Tc,  123 I, or any combination thereof. 
     
     
         8 . The compound of  claim 6 , wherein R 1  is selected from the group consisting of  11 C-methyl, optionally substituted C 1-6 alkyl, optionally substituted C 7-12 aralkyl, optionally substituted C 6-12 aryl, each of which may be substituted with one or more  11 C-methyl groups,  18 F,  99 Tc,  123 I,  125 I,  131 I, or a combination thereof. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is  11 C-methyl, C 1-6 alkyl substituted with one or more  18 F, or benzyl substituted with one or more  18 F. 
     
     
         10 . The compound of  claim 6 , wherein R 1  comprises one or more radioisotope suitable for use in radiation therapy. 
     
     
         11 . The compound of  claim 1 , wherein the compound is according to Formula III: 
       
         
           
           
               
               
           
         
         wherein Ar is a carbocyclic aromatic group having from 6 to about 18 carbon atoms and between 1 and about 3 rings which is substituted with one or more groups selected from halogen, alkyl, amino, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted benzoyloxy, and optionally substituted alkoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of  claim 11 , wherein the compound is according to Formula IV: 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, amino, mono and di alkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted fluoroalkyl, optionally substituted aryl, optionally substituted benzoyloxy, and optionally substituted alkoxy; and 
         n is an integer from about 1 to about 5. 
       
     
     
         13 . The compound of  claim 11 , wherein Ar comprises one or more positron emitting isotopes of  11 C,  18 F,  99 Tc,  123 I or any combination thereof. 
     
     
         14 . The compound of  claim 12 , wherein R 2  is selected from the group consisting of  11 C-methyl,  11 C-methoxy, optionally substituted C 1-6 alkyl, optionally substituted C 7-12 aralkyl, optionally substituted C 6-12 aryl, each of which may be substituted with one or more  11 C-methyl groups,  18 F,  99 Tc,  123 I,  125 I,  131 I, or a combination thereof. 
     
     
         15 . The compound of  claim 12 , wherein R 2  is phenyl substituted with one or more groups selected from hydroxy,  11 C-methoxy,  11 C-methyl,  18 F,  123 I, benzoyloxy which may be substituted with one or more fluoro groups, or a combination thereof. 
     
     
         16 . A compound of  claim 1  which has a binding affinity to NAALADase or PSMA of less than about 10 μM. 
     
     
         17 . A compound of  claim 1  which has a binding affinity to NAALADase or PSMA of less than about 1 μM. 
     
     
         18 . A compound of  claim 1  which has a binding affinity to NAALADase or PSMA of less than about 100 nM. 
     
     
         19 . A compound of  claim 1  which has a binding affinity to NAALADase or PSMA of less than about 10 nM. 
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of  claim 1 . 
     
     
         21 . A package comprising a pharmaceutical composition of  claim 20  in a container and further comprising indicia comprising at least one of:
 instructions for using the composition to image cells or tissues expressing at least one of NAALADase or PSMA, or 
 instructions for using the composition to image glutamatergic neurotransmission in a patient suffering from a stress-related disorder, or 
 instructions for using the composition to image prostate cancer. 
 
     
     
         22 . An imaging method comprising the steps of:
 providing a radiolabeled compound according to the formula:   
       
         
           
           
               
               
           
         
         
           wherein 
           R is selected from the group consisting of fluoroalkyl, aryl, benzyl, thiol, and alkylthiol, each of which is optionally substituted with an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkanoyl, or optionally substituted aralky, optionally substituted alkoxy, optionally substituted aralkyloxy, or optionally substituted phenoxy; 
           Q is hydrogen, optionally substituted alkyl, optionally substituted benzyl or optionally substituted phenyl; and 
           Z is Q or a tetrazole; or a pharmaceutically acceptable salt thereof; contacting cells or tissues with the radiolabeled compound; and making a radiographic image. 
         
       
     
     
         23 . The method of  claim 22 , wherein the imaging method is suitable for use in imaging glutamateric neurotransmission. 
     
     
         24 . The method of  claim 22 , wherein the imaging method is suitable for use in imaging presynaptic glutamatergic neurotransmission. 
     
     
         25 . The method of  claim 22 , wherein the imaging method is suitable for imaging of cancer which expresses at least one of NAALADase or PSMA. 
     
     
         26 . The method of  claim 22 , wherein the imaging method is suitable for imaging of prostate cancer. 
     
     
         27 . The method of  claim 26 , wherein the imaging method is suitable for imaging prostate cancer including metastases. 
     
     
         28 . The method of  claim 22 , wherein the imaging method is suitable for imaging angiogenesis. 
     
     
         29 . The method of  claim 28 , wherein the angiogenesis is associated with tumors, collagen vascular disease, cancer, stroke, vascular malformations, retinopathy, and normal tissue development. 
     
     
         30 . The method of  claim 22 , wherein the radiolabeled compound exhibits a target to non-target ratio of at least about 5:1. 
     
     
         31 . The method of  claim 22 , wherein the radiolabeled compound is stable in vivo. 
     
     
         32 . The method of  claim 22 , wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 120 minutes after administration. 
     
     
         33 . The method of  claim 22 , wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 60 minutes after administration. 
     
     
         34 . The method of  claim 22 , wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 30 minutes after administration. 
     
     
         35 . The method of  claim 22 , wherein the radiolabeled compound is detected by a gamma camera positron emission tomography (PET) or single photon emission tomography (SPECT). 
     
     
         36 . The method of  claim 22 , wherein the subject is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian. 
     
     
         37 . A compound which is 2-[3-(1-Carboxy-2- 11 C-methylsulfanyl-ethyl)-ureido]-pentanedioic acid. 
     
     
         38 . The compound of  claim 1 , wherein the compound is according to Formula V: 
       
         
           
           
               
               
           
         
         wherein Ar is a carbocyclic aromatic group having from 6 to about 18 carbon atoms and between 1 and about 3 rings which is substituted with one or more groups selected from halogen, alkyl, amino, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted benzoyloxy, and optionally substituted alkoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         39 . The compound of  claim 38 , wherein the compound is according to Formula VI: 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, amino, mono and di alkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted fluoroalkyl, optionally substituted aryl, optionally substituted benzoyloxy, and optionally substituted alkoxy; and 
         n is an integer from about 1 to about 5. 
       
     
     
         40 . The compound of  claim 38 , wherein Ar comprises one or more positron emitting isotopes of  11 C,  18 F,  99 Tc,  123 I or any combination thereof. 
     
     
         41 . The compound of  claim 39 , wherein R 2  is selected from the group consisting of  11 C-methyl,  11 C-methoxy, optionally substituted C 1-6 alkyl, optionally substituted C 7-12 aralkyl, optionally substituted C 6-12 aryl, each of which may be substituted with one or more  11 C-methyl groups,  18 F,  99 Tc,  123 I,  125 I,  131 I, or a combination thereof. 
     
     
         42 . The compound of  claim 39 , wherein R 2  is phenyl substituted with one or more groups selected from hydroxy,  11 C-methoxy,  11 C-methyl,  18 F,  123 I, benzoyloxy which may be substituted with one or more fluoro groups, or a combination thereof. 
     
     
         43 . The compound of  claim 1 , wherein the compound is according to Formula VII: 
       
         
           
           
               
               
           
         
         wherein 
         L is a chelating ligand suitable for coordination to Tc; 
         p is 0, or 1; and 
         n is an integer of from about 1 to about 6; or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The compound of  claim 43 , wherein the compound is according to Formula VIII: 
       
         
           
           
               
               
           
         
         where E is oxygen or absent. 
       
     
     
         45 . The compound of  claim 12 , wherein the compound is according to Formula IX: 
       
         
           
           
               
               
           
         
         wherein R 3  is a fluorescent dye which emits in the visible or near infrared spectrum. 
       
     
     
         46 . The compound of  claim 45 , wherein R 3  is FITC, a derivative thereof, carbocyanine, or a derivative thereof. 
     
     
         47 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 2-[3-(1-Carboxy-3- 11 C-methylsulfanyl-propyl)-ureido]-pentanedioic acid,   2-[3-(1-Methoxycarbonyl-3- 11 C-methylsulfanyl-propyl)-ureido]-pentanedioic acid,   2-[3-(1-Carboxy-2- 11 C-methylsulfanyl-ethyl)-ureido]-4-(1H-tetrazol-5-yl)-butyric acid,   2-{3-[Carboxy-(4- 11 C-methoxy-phenyl)-methyl]-ureido}-pentanedioic acid,   2-{3-[Carboxy-(4-fluoro-phenyl)-methyl]-ureido}-pentanedioic acid,   2-{3-[Carboxy-(3-fluoro-phenyl)-methyl]ureido}-pentanedioic acid,   2-{3-[Carboxy-(2-fluoro-phenyl)-methyl]-ureido}-pentanedioic acid,   2-[3-(1-Carboxy-4-fluoro-butyl)-ureido]-pentanedioic acid,   2-[3-(1-Carboxy-4-fluoro-3-methyl-butyl)-ureido]-pentanedioic acid,   2-{3-[1-Carboxy-2-(2-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(3-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(4-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(2-fluoro-ethylsulfanyl)-ethyl]-ureido}-pentanedioic acid,   2-(3-{1-Carboxy-2-[4-(2-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,   2-(3-{1-Carboxy-2-[4-(3-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,   2-(3-{1-Carboxy-2-[4-(4-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,   2-(3-{1-Carboxy-2-[4-(4-fluoromethyl-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,   2-[3-(1-Carboxy-2-{4-[4-(4-fluoro-butyl)-benzo yloxy]-phenyl}-ethyl)-ureido]-pentanedioic acid,   2-(3-{1-Carboxy-2-[4-(4-fluoro-benzyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,   2-{3-[1-Carboxy-2-(4-hydroxy-3-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(4-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(3-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(2-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(4-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid,   2-{3-[1-Carboxy-2-(3-iodo-phenyl)-ethyl]ureido}-pentanedioic acid, and   2-{3-[1-Carboxy-2-(2-iodo-phenyl)-ethyl]ureido}-pentanedioic acid,