DEVELOPMENT OF RADIOLIGANDS FOR THE IMAGING OF CARDIAC BETA-ADRENOCEPTORS USING SPECT .2. PHARMACOLOGICAL CHARACTERIZATION IN-VITRO AND IN-VIVO OF NEW I-123 LABELED BETA-ADRENOCEPTOR ANTAGONISTS

Cardiac beta-adrenoceptors are assumed to play a key role in chronic h eart failure. Although several radioligands labeled with C-11 or F-18 have been synthesized for imaging purposes with positron emission tomo graphy (PET), so far no optimal ligands are available to image cardiac beta-adrenoceptors using single photon emission tomography (SPECT), I n the present study, we characterized four new synthesized analogues o f the nonselective p-adrenoceptor antagonist -t-butylamino-2-hydroxypr opoxy)-benzimidazol-2-one (CGP12177) and one analogue of the nonselect ive beta-adrenoceptor antagonist penbutolol. Using classical in vitro displacement studies with left ventricular tissue of New Zealand White rabbits and [I-125] iodocyanopindolol as a radioligand, binding affin ity to the receptor was determined. From the four analogues, only (2'S ,2''E)- [4-(3'-(1'', yl-3''-Iodo-2''propenylamino)-2'-hydroxypropoxy)] - benzimidazol-2-one proved to have a high affinity, with K-i = 1.25 /- 0.09 nM, n = 3. The other analogues showed relatively low affinity, with K-i-values > 1 nM. The analogue of penbutolol (2-Iodophenoxy)]-3 '-(tert-butylamino)-2'-propanol) also showed a K-i value of 0.64 +/- 0 .26 nM, n = 3. Subsequently (2'S,2''E)-[4-(3'-( 1'', 1''-dimethyl-3''- Iodo-2''propenylamino)one and -(2-Iodophenoxy)]-3'-(tert-butylamino)-2 '-propanol were radioactively labeled with I-123 to study their biodis tribution in New Zealand White rabbits and to determine specific bindi ng. Significant uptake was observed in both lungs and left ventricles. However, both compounds showed high nonspecific binding in vivo becau se uptake of the radioligand could not be inhibited by preinjection of different (selective and nonselective-adrenoceptor antagonists and hy drophilic and lipophilic antagonists) antagonists. In conclusion, alth ough two analogues showed reasonable affinity in vitro for the recepto r, their binding in vivo proved to be largely nonspecific, suggesting that these two compounds are unsuitable for imaging purposes. However, because marked differences in affinity for the receptor were observed with only little structural changes between compounds, the present re sults offer future perspectives for the synthesis of a more specific r adioligand. Copyright (C) 1997 Elsevier Science Inc.