Contrast agents for myocardial perfusion imaging

Abstract

The present disclosure is directed, in part, to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a contrast agent which comprises a compound that binds MC-1, and an imaging moiety, and scanning the patient using diagnostic imaging.

1 . A contrast agent comprising an imaging moiety and a compound selected from an annonaceous acetogenin, a quinone acetogenin, a substituted chromone, and an open-chain deguelin analog. 
     
     
         2 . The contrast agent of  claim 1  of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
 o is 0 or 1; 
 p is 5, 6, 7, 8, 9, 10, 11, or 12; 
 --- is absent or a single bond; 
 when --- is absent, A and B are independently selected from hydrogen and an imaging moiety; 
 when --- is a single bond, A and B are each (C(R 1 ) 2 ) k ; 
 k is 1 or 2, provided that when A and B are each (C(R 1 ) 2 ) k , one k is 1 and the other is 1 or 2; 
 R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 , R 15 , and R 16  are independently at each occurrence hydrogen, hydroxy, or an imaging moiety; 
 R 3  is hydrogen, hydroxy, or an imaging moiety; 
 R 3′  is hydrogen; or 
 R 3  and R 3′ , together with the carbon atom to which they are attached, form C═O or C═CR 13 R 14 ; 
 R 6  is hydrogen, hydroxy, or an imaging moiety; 
 R 6′  is hydrogen; or 
 R 6  and R 6′ , together with the carbon atom to which they are attached, form C═O or C═CR 13 R 14 ; 
 R 9  is hydrogen, hydroxy, or an imaging moiety; 
 R 9′  is hydrogen; or 
 R 9  and R 9′ , together with the carbon atom to which they are attached, form C═O or C═CR 13 R 14 ; 
 R 11  is C 1 -C 6  alkyl; and 
 R 12 , R 13 , and R 14 , are independently hydrogen, C 1 -C 6  alkyl optionally substituted with an imaging moiety, arylalkyl, or an imaging moiety; 
 
       provided that at least one imaging moiety is present in formula (I). 
     
     
         3 . The contrast agent of  claim 2  wherein R 4  is an imaging moiety. 
     
     
         4 . The contrast agent of  claim 2  wherein R 5  is an imaging moiety. 
     
     
         5 . The contrast agent of  claim 2  wherein R 8  is an imaging moiety. 
     
     
         6 . The contrast agent of  claim 2  wherein R 9  is an imaging moiety. 
     
     
         7 - 10 . (canceled) 
     
     
         11 . The contrast agent of  claim 1  of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; 
 r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
 s is 0 or 1; 
 t is 5, 6, 7, 8, 9, 10, 11, or 12; 
 --- is absent or a single bond; 
 when --- is absent, D and E are independently selected from hydrogen and an imaging moiety; 
 when --- is a single bond, D and E are each (C(R 15 ) 2 ) u ; 
 u is 1 or 2, provided that when D and E are each (C(R 15 ) 2 ) u , one u is 1 and the other is 1 or 2; 
 R 15 , R 16 , R 18 , R 19 , R 21 , and R 22 , are independently at each occurrence hydrogen, hydroxy, or an imaging moiety; 
 R 17  is hydrogen, hydroxy, or an imaging moiety; 
 R 17′  is hydrogen; or 
 R 17  and R 17′ , together with the carbon atom to which they are attached, form C═O or C═CR 27 R 28 ; 
 R 20  is hydrogen, hydroxy, or an imaging moiety; 
 R 20′  is hydrogen; or 
 R 20  and R 20′ , together with the carbon atom to which they are attached, form C═O or C═CR 27 R 28 ; 
 R 23  is hydrogen, hydroxy, or an imaging moiety; 
 R 23′  is hydrogen; or 
 R 23  and R 23′ , together with the carbon atom to which they are attached, form C═O or C═CR 27 R 28 ; 
 R 24 , R 25 , and R 26  are independently hydrogen, C 1 -C 6  alkyl optionally substituted with an imaging moiety, C 1 -C 6  alkoxy, hydroxy, halo, or an imaging moiety; and 
 R 27  and R 28  are independently hydrogen, C 1 -C 6  alkyl optionally substituted with an imaging moiety, arylalkyl, an imaging moiety; 
 
       provided that at least one imaging moiety is present in formula (II). 
     
     
         12 . The contrast agent of  claim 11  wherein R 18 , R 19 , R 22 , or R 23  is an imaging moiety. 
     
     
         13 . The contrast agent of  claim 11  wherein R 22  is an imaging moiety. 
     
     
         14 . (canceled) 
     
     
         15 . The contrast agent of  claim 1  of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein
 G is —S—, —O—, 
 
       
         
           
           
               
               
           
         
         J is S, C(R 37 ) 2 , or O; 
            is a single or double bond; and 
         R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , and R 42  are independently at each occurrence hydrogen, C 1 -C 6  alkyl optionally substituted with an imaging moiety, C 1 -C 6  alkoxy optionally substituted with an imaging moiety, or an imaging moiety; provided that when   is a double bond, R 31  and R 32  are absent; and 
       
       provided at least one imaging moiety is present in formula (III). 
     
     
         16 - 21 . (canceled) 
     
     
         22 . The contrast agent of  claim 1  of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein
 n, m, and o are independently 1, 2, 3, or 4; 
 Z is O, S, or NR 46 ; 
 R 45  is an imaging moiety or C 1 -C 4  alkyl optionally substituted with an imaging moiety; 
 R 46  is hydrogen or C 1 -C 3  alkyl; 
 Ar is phenyl, furyl, thienyl, oxazolinyl, isoxazolinyl, thiazolyl, isothiazolyl, pyridyl, naphthyl, pyrimidinyl, or pyrazinyl; 
 G is absent or O; and 
 L is an imaging moiety; 
 
       provided that when G is absent, o is 3. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The contrast agent of  claim 1  wherein the imaging moiety is a radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity for use in fluorescence imaging, or a light-active entity for use in optical imaging. 
     
     
         26 . The contrast agent of  claim 25  wherein the paramagnetic species for use in MRI imaging is Gd 3+ , Fe 3+ , In 3+ , or Mn 2+ . 
     
     
         27 . The contrast agent of  claim 25  wherein the echogenic entity for use in ultrasound imaging is a fluorocarbon encapsulated surfactant microsphere. 
     
     
         28 . The contrast agent of  claim 25  wherein the radioisotope for nuclear medicine imaging is  11 C,  13 N,  18 F,  123 I,  124 I,  125 I,  99m Tc,  95 Tc,  111 In,  76 Br,  62 Cu,  64 Cu,  67 Ga, or  68 Ga. 
     
     
         29 . The contrast agent of  claim 28  wherein the imaging moiety is  18 F. 
     
     
         30 . The contrast agent of  claim 28  wherein the imaging moiety is  99m Tc. 
     
     
         31 . A method of imaging myocardial perfusion comprising administering to a patient a contrast agent which comprises an imaging moiety and a compound selected from an annonaceous acetogenin, a quinone acetogenin, a substituted chromone and an open-chain deguelin analog; and scanning the patient using diagnostic imaging. 
     
     
         32 . The method of  claim 31  wherein the imaging moiety is a radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity for use in fluorescence imaging, or a light-active entity for use in optical imaging.