Compositions, methods, and systems for the synthesis and use of imaging agents

Abstract

The present invention relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, the imaging agent is enriched in 18 F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs. In some embodiments, methods and compositions for assessing perfusion and innervation mismatch in a portion of a subject are provided.

1 . A compound of the formula:
   R 0 —Ar-L-R 1  
   wherein
 Ar is substituted or unsubstituted, monocyclic or bicyclic aryl or substituted or unsubstituted, monocyclic or bicyclic heteroaryl; 
 L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene; substituted or unsubstituted, cyclic or acyclic alkenylene; substituted or unsubstituted, cyclic or acyclic alkynylene; or substituted or unsubstituted, cyclic or acyclic heteroaliphatic; 
 R 1  is a substituted or unsubstituted nitrogen-containing moiety; and 
 R 0  is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR A2 )OR A1 , —C(═NR A2 )SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR A2 )SR A1 , —OC(═NR A2 )N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR A2 )OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A2 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, or —NO 2    
 each occurrence of R A1  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2  groups are joined to form an optionally substituted heterocyclic ring; and 
 R 0  or R 1  is substituted with an imaging moiety selected from the group consisting of  18 F,  76 Br,  124 I, and  131 I, or is associated with an imaging moiety selected from the group consisting of  64 Cu,  89 Zr,  99m Tc, and  111 In through a chelator, or is an imaging moiety selected from the group consisting of  18 F,  76 Br,  124 I, and  131 I; 
 or a salt thereof; 
 provided the compound is not of the formula 
   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 - 124 . (canceled) 
     
     
         125 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene; substituted or unsubstituted, cyclic or acyclic alkenylene; substituted or unsubstituted, cyclic or acyclic alkynylene; or substituted or unsubstituted, cyclic or acyclic heteroaliphatic; 
 R 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         each occurrence of R B  is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group, provided at least two R B  are hydrogen;
 R 2  and R 6  are hydrogen; 
 each of R 3 , R 4  and R 5  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR A2 )OR A1 , —C(═NR A2 )SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR A2 )SR A1 , —OC(═NR A2 )N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR A2 )OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A2 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, or —NO 2 ; or any two adjacent R 3 , R 4  and R 5  are joined to form an optionally substituted or unsubstituted carbocyclic, heterocyclic, aryl, or heteroaryl ring; 
 each occurrence of R A1  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2  groups are joined to form an optionally substituted heterocyclic ring; and 
 wherein R 4  is substituted with an imaging moiety selected from the group consisting of  18 F,  76 Br, and  124 I; or is associated with an imaging moiety selected from the group consisting of  64 Cu,  89 Zr,  99m Tc, and  111 In through a chelator; or is  124 I; 
 or a salt thereof 
 with the proviso that if one of R 3  or R 5  is Cl, Br, or CF 3 , then the other of R 3  or R 5  is not H; and 
 provided the compound is not of the formula: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         126 . A compound of  claim 125 , where R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         127 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein each occurrence of R B  is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group, provided at least two R B  are hydrogen. 
     
     
         128 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R B  is hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group. 
     
     
         129 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         130 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein each occurrence of R B  is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group, provided at least two R B  are hydrogen. 
     
     
         131 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R B  is hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group. 
     
     
         132 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         133 . A compound of  claim 125 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         134 . A compound of  claim 125 , where R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         135 - 281 . (canceled) 
     
     
         282 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 R 9  and R 10  are independently selected from the group consisting of H, —OR 11 , F, Cl, Br, I, —CF 3 , alkyl(C 1 -C 4 ), and imaging moiety (I m ); 
 R 11 , R 12  and R 13  are selected from the group consisting of H, alkyl, and aryl; and 
 W and X are independently selected from the group consisting of H, —OR 4 , —N(R 11 ) 2 , F, Cl, Br, —CF 3 , I m , aryl, and heteroaryl; 
 wherein A) Y and Z are independently selected from the group consisting of —CH—, —CH 2 —, —O—, —N—, —NR 11 —, and —CH═CH— when a linking group Q between Y and Z is present or absent, wherein Q is selected from the group consisting of —CH—, —CH 2 —, —CR 11 —, —N—, —NH—, —NR 11 —, —O—, and —S—; or 
 B) Y and Z are independently selected from the group consisting of H, —OR 4 , —N(R 11 ) 2 , F, Cl, Br, —CF 3 , I m , aryl, and heteroaryl when linking group Q is absent; 
 wherein I m  is selected from the group consisting of  18 F,  76 Br,  124 I, and  131 I, and is present in either W—Z or R 9 -R 13 ; 
 provided the compound is not of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         283 - 284 . (canceled) 
     
     
         285 . A compound of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         286 . A pharmaceutical composition comprising a compound of  claim 285 , or a salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         287 . (canceled) 
     
     
         288 . A method of imaging cardiac innervation comprising steps of:
 administering an effective amount of a compound of  claim 285  or a salt thereof to a subject;   detecting radiation emitted by the compound; and   forming an image therefrom.   
     
     
         289 . A method of imaging a subject comprising:
 administering a compound of  claim 285  or a salt thereof; and   acquiring at least one image of a portion of the subject.   
     
     
         290 . A method of detecting norepinephrine transporter (NET) in a portion of a subject, the method comprising:
 administering a compound of  claim 285  or a salt thereof; and   acquiring at least one image of the portion of the subject, wherein the image detects NET in the subject.   
     
     
         291 . A method of selecting an antiarrhythmic agent and/or determining the dose of an antiarrhythmic agent for administration to a subject, the method comprising
 administering to the subject the compound of  claim 285  or a salt thereof;   acquiring at least one image of a portion of the subject;   selecting the antiarrhythmic agent and/or determining the dose of an antiarrhythmic agent for administration to a subject based on the at least one first image.   
     
     
         292 - 296 . (canceled) 
     
     
         297 . The method of  claim 291 , wherein a reduced dose of an antiarrhythmic agent that induces electrophysiological changes in a subject's heart is prescribed based on the at least one first image indicating presence of cardiac denervation. 
     
     
         298 . A method comprising
 administering to the subject the compound of  claim 285 ;   or a salt thereof;   acquiring at least one image of a portion of the subject; and   identifying   (i) a subject to be treated with an antiarrhythmic agent that does not induce electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image,   (ii) a subject to be treated with a reduced dose of an antiarrhythmic agent that induces electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image, and/or   (iii) a subject in need of a dose reduction of an antiarrhythmic agent that induces electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image.   
     
     
         299 - 373 . (canceled)