CHARACTERIZATION OF [H-3] CERANAPRIL RECOGNITION SITES IN RAT AND HUMAN BRAIN-TISSUE

The present studies assessed the nature of the recognition site for [H-3]ceranapril in tissue from rat and human brain. [H-3]Ceranapril exhibited high affinity saturable specific (defined by 1-mu-M captopril) binding to homogenates of tissue from both rat and human brain (mean pK(d) values between 8.42 and 8.69). High binding densities were observed in rat striatum and homogenates of tissue from human caudate (B(max) values 3317 +/- 192 and 1900 +/- 110 fmol/mg protein respectively), with comparatively low densities in cortical tissues. In kinetic experiments, association of [H-3]ceranapril to homogenates of rat and human cortex was found to be rapid and fully reversible (K+1 = 6 x 10(5) M-1 sec-1 and 2.4 x 10(6) M-1 sec-1, K-1 = 7.6 x 10(-3) sec-1 and 4.5 x 10(-3) sec-1 respectively). In competition studies, lisinopril, captopril, unlabelled ceranapril, epicaptopril and fosinopril, all competed to a similar extent and with similar rank order of potency for the binding of [H-3]ceranapril to homogenates of both rat and human brain. In in vivo studies, pretreatment of rats with either captopril or lisinopril (15-mu-g/250 g) significantly reduced the content of tritium in brain, as measured 20 min after intravenous administration of [H-3]ceranapril. From these experiments [H-3]ceranapril appears to selectively label, with high affinity, the inhibitor binding site of angiotensin converting enzyme and this site appears to be similar in both species studied.