Agents for the Molecular Imaging of Serine-Protease in Human Pathologies

Abstract

The present invention is directed to the use of an irreversible ligand of a serine protease selected from the group consisting of leukocyte elastase, thrombin, tissue plasminogen activator (t-PA) and plasmin for the molecular imaging of said serine protease and the diagnosis of pathophysiological conditions associated with said serine protease activity.

1 - 11 . (canceled) 
     
     
         12 . A leukocyte elastase-targeted molecular imaging agent comprising at least one irreversible peptide ligand of leukocyte elastase associated with at least one detectable moiety wherein said irreversible peptide ligand has the general formula (I):
   P-X-Y-Z-Pro-Val-cmk (I)   wherein:   P is a protective group   X is Gly, Ala or beta-Ala   Y is Gly, Ala or Leu   Z is Ala, Val, Ile, or Leu.   
     
     
         13 . The leukocyte elastase-targeted molecular imaging agent of  claim 12 , wherein said protective group is Acetyl (Ac) or tButyloxycarbonyl (Boc). 
     
     
         14 . The leukocyte elastase-targeted molecular imaging agent of  claim 12 , wherein the at least one irreversible peptide ligand of a leukocyte elastase is covalently bound through a Gly residue with a metal-chelating moiety. 
     
     
         15 . The leukocyte elastase-targeted molecular imaging agent of  claim 14 , wherein the metal-chelating moiety is 1, 4, 7, 10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), diethylene triaminepentaacetic acid (DTPA), 1,4,7-triaza-cyclononane N,N,N″-triacetic acid (NOTA) or 6-hydrazinopyridine-3-carboxylic acid (HYNIC). 
     
     
         16 . The leukocyte elastase-targeted molecular imaging agent of  claim 14 , wherein the metal-chelating moiety is complexed with a radionuclide metal or a paramagnetic metal ion. 
     
     
         17 . The leukocyte elastase-targeted molecular imaging agent of  claim 16 , wherein the radionuclide metal is gallium-68 (68Ga), technetium-99m (99mTc), gallium-67 (67Ga), yttrium-91 (91Y), indium-111 (111In), rhenium-186 (186Re), or thallium-201 (201Tl). 
     
     
         18 . The leukocyte elastase-targeted molecular imaging agent of  claim 16 , wherein the paramagnetic metal ion is gadolinium III (Gd3+). 
     
     
         19 . The leukocyte elastase-targeted molecular imaging agent of  claim 12 , wherein the at least one irreversible peptide ligand of a leukocyte elastase is covalently bound through a benzylthiourea with a metal-chelating moiety. 
     
     
         20 . The leukocyte elastase-targeted molecular imaging agent of  claim 19 , wherein the metal-chelating moiety is DOTA, DTPA or NOTA. 
     
     
         21 . A pharmaceutical composition comprising at least one leukocyte elastase-targeted molecular imaging agent according to  claim 12  and at least one pharmaceutically acceptable carrier. 
     
     
         22 . A method of molecular imaging leukocyte elastase in a patient in need thereof, comprising:
 a) administering to the patient an effective amount of a leukocyte elastase-targeted molecular imaging agent comprising at least one irreversible peptide ligand of a leukocyte elastase bound to at least one detectable moiety via a spacer, whereby said leukocyte elastase-targeted molecular imaging agent binds to leukocyte elastase present in the patient, wherein said irreversible peptide ligand has formula (I):
   P-X-Y-Z-Pro-Val-cmk (1) 
 wherein: 
   P is a protective group
 X is Gly, Ala or beta-Ala 
 Y is Gly, Ala or Leu 
 Z is Ala, Val, Ile, or Leu. 
   wherein said detectable moiety is detectable by a molecular imaging technique selected from the group consisting of Magnetic Resonance Imaging (MRI), planar scintigraphy (PS), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), or any combination of these techniques and   b) detecting the leukocyte elastase-targeted imaging agent bound to leukocyte elastase present in the patient using said molecular imaging technique.