Novel fluorine-18 labeled rhodamine derivatives for imaging with positron emission tomography

Abstract

The present invention is directed toward novel fluorine-18 labeled rhodamine dye derivatives and methods of making the same. The present invention is also directed toward methods of using novel fluorine-18 labeled rhodamine dye derivatives as positron emission tomography imaging agents and myocardial perfusion imaging agents.

What is claimed is: 
     
         1 . A compound comprising an  18 F labeled rhodamine derivative according to formula I or II: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbonyl, acylamino, halogen, halogen radioisotope, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, isothiocyano and a compound of formula III 
       
       
         
           
           
               
               
           
         
         wherein R 10 , R 11 , R 12 , R 13  and R 14  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbonyl, acylamino, halogen, halogen radioisotope, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino and isothiocyano; 
         wherein R 2  and R 3 , taken together with the nitrogen atom to which they are attached, may optionally form a substituted or unsubstituted heterocyclic ring system; 
         R 2  and R 10 , taken together with the atoms to which they are attached, may optionally form a 5- or 6-membered heterocyclic ring; 
         R 2  and R 1 , taken together with the atoms to which they are attached, may optionally form a 5- or 6-membered heterocyclic ring; and 
         R 3  and R 4 , taken together with the atoms to which they are attached, may optionally form a 5- or 6-membered heterocyclic ring or a substituted or unsubstituted heterocyclic ring system; 
         A 1  is carbon or nitrogen, if A 1  is nitrogen, then R 6  is absent; 
         R 6  is absent or selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbonyl, acylamino, halogen, halogen radioisotope, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, isothiocyano; 
         R 7 , R 8  and R 9  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbonyl, acylamino, halogen, halogen radioisotope, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, isothiocyano; 
         R 15  is independently selected from the group consisting of  18 F-labeled substituted or unsubstituted alkyl,  18 F-labeled substituted or unsubstituted alkenyl,  18 F-labeled substituted or unsubstituted alkynyl,  18 F-labeled substituted or unsubstituted heterocycloalkyl,  18 F-labeled substituted or unsubstituted alkoxy,  18 F-labeled substituted or unsubstituted carbonyl,  18 F-labeled acylamino, halogen radioisotope,  18 F-labeled substituted or unsubstituted aryl,  18 F-labeled substituted or unsubstituted heteroaryl,  18 F-labeled substituted or unsubstituted amino,  18 F-labeled substituted or unsubstituted alkylamino,  18 F-labeled substituted or unsubstituted arylamino,  18 F-labeled isothiocyano, and —(CH 2 CH 2 O) m CH 2 CH 2   18 F, wherein m is 1-50; 
         R 16  is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbonyl, acylamino, halogen, halogen radioisotope, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, isothiocyano; and 
       
       A- is an anion. 
     
     
         2 . The compound of  claim 1 , wherein R 15  is  18 F-labeled substituted or unsubstituted alkyl. 
     
     
         3 . The compound of  claim 2  wherein R 15  is —(CH 2 ) n CH 2   18 F, wherein n is 1-5. 
     
     
         4 . The compound of  claim 3 , wherein R 15  is —CH 2 CH 2 CH 2   18 F. 
     
     
         5 . The compound of  claim 1 , wherein R 15  is —(CH 2 CH 2 O) m CH 2 CH 2   18 F, wherein m is 1-4. 
     
     
         6 . The compound of  claim 5 , R 15  is —CH 2 CH 2 OCH 2 CH 2   18 F. 
     
     
         7 . The compound of  claim 1 , wherein R 2  and R 3  are alkyl; R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are hydrogen; and A 1  is carbon. 
     
     
         8 . The compound of  claim 7 , wherein R 2  is ethyl. 
     
     
         9 . The compound of  claim 7 , wherein R 3  is ethyl. 
     
     
         10 . The compound of  claim 1 , wherein R 2  and R 4  are alkyl; R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9  are hydrogen; and A 1  is carbon. 
     
     
         11 . The compound of  claim 10 , wherein R 2  is ethyl. 
     
     
         12 . The compound of  claim 10 , wherein R 3  is ethyl. 
     
     
         13 . The compound of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are hydrogen; and A 1  is carbon. 
     
     
         14 . The compound of  claim 1 , wherein R 3  and R 4 , taken together with the atoms to which they are attached, form a 6-membered heterocyclic ring and R 2  and R 1 , taken together with the atoms to which they are attached, form a 6-membered heterocyclic ring. 
     
     
         15 . The compound of  claim 1 , wherein R 4  is methyl; and R 2  and R 3  are each independently hydrogen or alkyl. 
     
     
         16 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method of obtaining a positron emission image of a portion of a mammal, comprising the steps of:
 administering to the mammal a compound of  claim 1 , and   acquiring a positron emission image of a portion of a mammal.   
     
     
         18 . The method of  claim 17  wherein the mammal is human. 
     
     
         19 . The method of  claim 17  wherein the portion of a mammal is the myocardium. 
     
     
         20 . A method of imaging myocardial perfusion comprising:
 administering to the patient a compound of  claim 1 , and   scanning the patient using diagnostic imaging.