CHEMISTRY OF BIFUNCTIONAL PHOTOPROBES .2. CHEMICAL AND PHOTOCHEMICAL MODIFICATION OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS - IMPLICATIONS IN THE DEVELOPMENT OF CARDIAC RADIONUCLIDE IMAGING AGENTS

The synthesis and biological activity of functionalized lisinopril, a potent angiotensin converting enzyme (ACE) inhibitor is described. Sel ective functionalization of lisinopril is achieved at the secondary am ino position by a photochemical method, whereas esterfication of the c arboxylic groups and modification at the primary amino group is achiev ed by chemical methods. Autoradiographic investigations using competit ive I-125 radioactive binding assays with the modified lisinopril reve al that the terminal amino group modification enhanced the binding to ACE, whereas the secondary amino group functionalization did not diffe r significantly from the binding properties of native lisinopril. Howe ver, esterification of the carboxyl groups reduced the inhibitory pote ntency from nM to mu M. These results suggest that lisinopril can be d erivatized with preservation of inhibition potency toward ACE. These m odifications may find utility in the development of photoaffinity labe ling agents for ACE or to incorporate bifunctional chelating agents ca rrying diagnostic radiometals for the development of cardiac imaging a gents. (C) 1997 Academic Press.