Boat tropanes

Abstract

Radiopharmaceutical compounds are disclosed. A tropane compound is linked through the N atom at the 8-position to a chelating ligand capable of complexing technetium or rhenium to produce a neutral labeled complex that selectively binds to the dopamine transporter over the serotonin transporter with a ratio of 10 or more. These compounds can be prepared as separate diastereoisomers as well as a mixture of diastereoisomers. Also disclosed are radiopharmaceutical kits for preparing the labeled radiopharmaceutical compounds.

1 . A radiopharmaceutical compound which is capable of complexing with  99m Tc, said compound having the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is α or β and is selected from COOR a , COR a , and CON(CH 3 )OR a ;  
 R 2  is α or β and is selected from the group consisting of C 6 H 4 X, C 6 H 3 XY, C 10 H 7 X, and C 10 H 6 XY;  
 R a  is C 1 -C 5  alkyl;  
 X and Y are independently selected from the group consisting of R a , H, Br, Cl, I, F, OH, and OCH 3 ;  
 L is —(CH 2 ) n  where n is an integer from 1 to 6, or —(CH 2 ) n —(aryl, arylalkyl, ethenyl or ethynyl)-(CH 2 ) m  -where m and n are integers and the sum of n plus m is an integer from 1 to 6; and  
 Ch is a tridentate or tetradentate chelating ligand that forms a neutral complex with technetium or rhenium.  
 
     
     
         2 . A compound according to  claim 1  labeled with a radionuclide that is complexed with the chelating ligand.  
     
     
         3 . A compound according to  claim 2 , wherein the radionuclide is  99m Tc.  
     
     
         4 . A compound according to  claim 2 , wherein the radionuclide is rhenium.  
     
     
         5 . A compound according to  claim 1 , wherein the tropane analog has a 3α-group.  
     
     
         6 . A compound according to  claim 1 , wherein the tropane analog has a 3β-group.  
     
     
         7 . A compound according to  claim 1 , wherein the chelating ligand comprises a bisamido-bisthiol group, a monoamide, monoamino-bisthiol group or a bisamino-bisthiol group covalently attached to linker L.  
     
     
         8 . (canceled)  
     
     
         9 . A compound according to  claim 1 , wherein the chelating ligand is N-(2-((2-((triphenylmethyl)thio)-ethyl)amino)acetyl)-S-(triphenylmethyl)-2-aminoethanethiol.  
     
     
         10 .- 17 . (canceled)  
     
     
         18 . A method for detecting the density of tropane recognition sites in a mammal as an indication of neurodegenerative or neuropsychiatric disorders characterized by changes in the density of dopamine transporters or dopamine neurons, said method comprising providing in a suitable pharmacological carrier a radiopharmaceutical compound according to  claim 1  labeled with  99m Tc, injecting the compound into the mammal and scanning the mammal using a radiodiagnostic imaging apparatus.  
     
     
         19 . A method for monitoring in a mammal neurodegenerative or neuropsychiatric disorders characterized by changes in the density of dopamine transporters or dopamine neurons, said method comprising providing in a suitable pharmacological carrier a radiopharmaceutical compound according to  claim 1  labeled with  99m Tc, injecting the compound into the mammal and scanning the mammal using a radiodiagnostic imaging apparatus.  
     
     
         20 . A radiopharmaceutical kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed, sterile, apyrogenic vial containing a radiopharmaceutical compound of  claim 1  and a reducing agent for labeling said compound with a radionuclide.  
     
     
         21 . (canceled)  
     
     
         22 . A compound having the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is α or β and is selected from COOR a , COR a , and CON(CH 3 )OR a ;  
 R 2  is α and is selected from C 6 H 4 X, C 6 H 3 )(Y, C 10 H 7 X, and C 10 H 6 XY;  
 R a  is a C 1 -C 5  alkyl;  
 X and Y are independently selected from R a , H, Br, Cl, I, F, OH, and OCH 3 ;  
 wherein the compound is in the 1R or 1S configuration;  
 and wherein N 8  is substituted with either H or CH 3 .