Radioligands for the TRP-M8 receptor and methods therewith

Abstract

One embodiment of the invention is a composition that comprises a radioactive [ 18 F], [ 76 Br]-, [ 77 Br]-, [ 211 At]-, [ 123 I], [ 125 I], or [ 131 I]-N-radioistope-labeled-aryl-alkyl-alkylcarboxamide molecule. The composition binds to the transient receptor potential-M8 (TRP-M8) receptor of cells. The TRP-M8 receptor is selectively expressed in sensory neurons and in malignant tissues such as prostate cancer cells. The [ 18 F], [ 76 Br]-, [ 77 Br]-, [ 211 At]-, [ 123 I], [ 125 I], or [ 131 I]-N-radioistope-labeled-aryl-alkyl-alkylcarboxamide ligand may be used for radioreceptor binding studies, for diagnostic studies, and for radiotherapy of cancerous tissues. Affinity of the N-radioistope-labeled-aryl-alkyl-alkylcarboxamide ligand for the TRP-M8 receptor confers selectivity and specificity in delivering lethal radiation to the diseased cells.

1 . A N-radioisotope-labeled-aryl-alkyl-alkylcarboxamide ligand wherein the alkyl moiety of the alkylcarboxamide is a cycloalkane radical having from 7 to about 14 carbons and with one to three C 1  to C 5  normal or branched alkyl substituents, the radioligand having a high affinity to TRP-M8 receptors in cells and tissues and having a specific activity of at least 20 Ci/mmol or greater, wherein the TRP-M8 affinity is characterized by a Kd of about 1×10 −5  or less.  
   
   
       2 . The radioligand as in  claim 1  wherein the radioisotope label is covalently bound in the molecule.  
   
   
       3 . The radioligand as in  claim 2  wherein the radioisotope label is selected from astatine, bromine, fluorine, iodine, astatide, bromide, fluoride, or iodide nadionuclides.  
   
   
       4 . The radioligand as in  claim 1  wherein the specific activity is about 20 Ci/mmol or greater and the radioisotope moiety emits alpha, beta or gamma radiation.  
   
   
       5 . A composition comprising a radioligand, the radioligand being a N-radioistope-labeled-aryl-alkyl-alkylcarboxamide of Formula 1:  
       R—(C═O)—N(H or CH 3 )—R′—Y  Formula 1  
     where (a) R is a saturated or monoethylenically unsaturated alkyl-substituted cyclic alkyl radical containing a total of 7 to about 14 carbon atoms and is selected from the group consisting of cyclopentanes, cyclohexanes, cycloheptanes, and cyclooctanes, each cyclic alkyl radical containing from 1 to 3 C 1 -C 5  normal or branched alkyl substituents, 
 (b) R′ is a normal or branched C 1 -C 3  carbon bridge with an optional hydroxy, and  
 (c) Y is an aromatic radical containing one to four substituents of R 1  or R 2 , and one to three substituents of X, wherein 
 R 1  is selected from the group hydrogen, hydroxyl, C 1 -C 5  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  carboxyalkyl, C 1 -C 4  carbonylalkylester, C 1 -C 3  oxycarbonylalkyl, C 1 -C 3  hydroxyalkyl,  
 R 2  is selected from the group —SO 2 NH-pyrimidine, —SO 3 —(H, Me or Et), or —CH 2 —SO 3 —(H, Me or Et), acetyl, C 1 -C 3  hydroxyalkyl, trifluoromethyl, nitro, cyano, halo, and  
 X is selected from the group [ 18 F]—, [ 123 I]—, [ 125 I]—, [ 131 I]— [ 76 Br]— [ 77 Br]— and [ 211 At]—.  
 
 
   
   
       6 . The composition as in  claim 5  wherein the cycloalkyl radical of the radioligand is ((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)-.  
   
   
       7 . The composition as in  claim 5  wherein the radioligand is a single enantiomer with its chiral center in R′.  
   
   
       8 . The composition as in  claim 5  wherein the radioligand has a specific activity of about 20 Ci/mmol or greater and emits alpha, beta or gamma radiation.  
   
   
       9 . The composition as in  claim 5  wherein the radioligand is a ligand for the TRP-M8 receptor.  
   
   
       10 . A diagnostic method, comprising: providing a radioligand, the radioligand being a N-radioistope-labeled-aryl-alkyl-alkylcarboxamide of Formula 1:  
       R—(C═O)—N(H or CH 3 )—R′—Y  Formula 1  
     where (a) R is a saturated or monoethylenically unsaturated alkyl-substituted cyclic alkyl radical containing a total of 7 to about 14 carbon atoms and is selected from the group consisting of cyclopentanes, cyclohexanes, cycloheptanes, and cyclooctanes, each cyclic alkyl radical containing from 1 to 3 C 1 -C 5  normal or branched alkyl substituents, 
 (b) R′ is a normal or branched C 1 -C 3  carbon bridge with an optional hydroxy, and  
 (c) Y is an aromatic radical containing one to four substituents of R 1  or R 2 , and one to three substituents of a radio label X, wherein 
 R 1  is selected from the group hydrogen, hydroxyl, C 1 -C 5  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  carboxyalkyl, C 1 -C 4  carbonylalkylester, C 1 -C 3  oxycarbonylalkyl, C 1 -C 3  hydroxyalkyl,  
 R 2  is selected from the group —SO 2 NH-pyrimidine, —SO 3 —(H, Me or Et), or —CH 2 —SO 3 —(H, Me or Et), acetyl, C 1 -C 3  hydroxyalkyl, trifluoromethyl, nitro, cyano, halo, and  
 X is selected from the group [ 18 F]—, [ 123 I]—, [ 125 I]—, [ 131 I]— [ 76 Br]— [ 77 Br]— and [ 211 At]—;  
 contacting the radioligand with cells or tissues under conditions sufficient to permit specific binding between the radioligand and TRP-M8 receptors if said receptors are carried by the cells or tissues; and,  
 examining the cells or tissues for presence of the radio lable X.