Labelled glutamine and lysine analogues

Abstract

Synthetic analogues of lysine and glutamine are provided which function as substrates for the fibrin-stabilising enzyme Factor XIIIa even when labelled with a detectable moiety. The use of suitable protecting groups provides compounds which possess reduced susceptibility to in vivo metabolism especially by peptidases, and are hence useful agents for the diagnosis of thrombosis, embolism, atherosclerosis, inflammation or cancer.

1 - 16 . (canceled)  
     
     
         17 . A compound of formula:  
         Y—(CR 2 ) n —X—NHJ  
       where: 
 X is C═O or —CR 2 —;  
 n is an integer of value 1 to 6;  
 Y is R 1 R 2 CR— where one of R 1  and R 2  is —NH(B) p Z 1  and the other is —CO(B) q Z 2  where p and q are integers of value 0 to 45, and  
 each B is independently chosen from Q or an amino acid residue,  
 where Q is a cyclic peptide;  
 Z 1  and Z 2  are metal complexing agents (L) or other protecting groups which are biocompatible groups which inhibit or suppress in vivo metabolism of the peptide;  
 J and each R group are independently chosen from H, C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, C 1-4  alkoxyalkyl or C 1-4  hydroxyalkyl; with the provisos that:  
 (i) the total number of amino acid residues in the R 1  and R 2  groups does not exceed 45;  
 (ii) when X is CR 2  then Z 2  is a metal complexing agent (L);  
 (iii) at least one of R 1  and R 2  bears at least one detectable moiety suitable for diagnostic imaging of the human body chosen from a non-metallic radioisotope or a radiometal;  
 (iv) R 1  or R 2  includes one or more peptide fragments of α 2 -antiplasmin, fibronectin, beta-casein, tetanus, amyloid, trappin and polyglutamine residues, said peptide fragment containing at least three amino acid residues.  
 
     
     
         18 . The compound of  claim 17  where the peptide fragment of proviso (iv) is from α 2 -antiplasmin.  
     
     
         19 . The compound of  claim 18  where the amino acid in the 2-position from the peptide N-terminus is glutamine.  
     
     
         20 . The compound of  claim 17  where J is H.  
     
     
         21 . The compound of  claim 20  of formula:  
         Y—(CR 2 ) x —(CH 2 ) 2 CONH 2  or Y—(CR 2 ) y —(CH 2 ) 4 NH 2    
       where x is an integer of value 0 to 4, and y is an integer of value 0 to 3.  
     
     
         22 . The compound of  claim 17  where at least one of Z 1  and Z 2  is a metal complexing agent.  
     
     
         23 . The compound of  claim 22  where Z 2  is a metal complexing agent and Z 1  is not a metal complexing agent.  
     
     
         24 . A metal complex of the compound of  claim 22 .  
     
     
         25 . The metal complex of  claim 24  where the metal is a radiometal.  
     
     
         26 . The radiometal complex of  claim 25  where the radiometal is  99m Tc.  
     
     
         27 . A preparation for human administration comprising the compound of  claim 17 .  
     
     
         28 . A kit comprising the compound of  claim 17  for use in the preparation of the metal complex of compound of  claim 17  where at least one of Z 1  and Z 2  is a metal complexing agent.  
     
     
         29 . Use for the diagnosis of sites of thrombosis or embolism of a compound of formula:  
         Y—(CR 2 ) n —X—NHJ  
       where: Y, X, R n and J are as defined in  claim 17 .  
     
     
         30 . Use for the diagnosis of sites of thrombosis or embolism of a radiometal complex of the compound defined in  claim 26 , wherein at least one of Z 1  and Z 2  is a metal complexing agent.