CHARACTERIZATION OF SPECIFIC BINDING OF [I-125] L-762,459, A SELECTIVE ALPHA(1A)-ADRENOCEPTOR RADIOLIGAND TO RAT AND HUMAN TISSUES

L-762,459 -amino}-propyl)-4-phenyl-1-piperidine-4-carboxylic acid meth yl ester), an analog of a series of dihydropyridines previously report ed to be selective alpha(1A)-adrenoceptor subtype antagonists was foun d to have alpha(1A)-adrenoceptor subtype selectivity (K-i (nM), la = 1 .3, Ib = 240, Id = 280). Specific [I-125]L-762,459 binding was detecte d in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the alpha(1A)-adrenoceptor subtype, but not in tissues known to contain alpha(1B)-adrenoceptor (spleen, l iver) and alpha(1D)-adrenoceptor (aorta). Scatchard analysis of [I-125 ]L-762,459 binding in rat cerebral cortex and prostate indicated a sin gle binding site with a K-d of 0.7 nM and B-max of 11 (cerebral cortex ) and 1 (prostate) pmole/g tissue. Specific and saturable [I-125]L-762 ,459 binding was also found in human cerebral cortex, liver, prostate and vas deferens (K-d = 0.2-0.4 nM, B-max = 0.4-4 pmole/g tissue). The specific binding in rat and human tissues was competed by non-selecti ve alpha(1)-adrenoceptor compounds (K-i values in nM, prazosin (0.14-1 .2), terazosin (1.8-5.9) and phentolamine (2.4-11)) and selective alph a(1A)-adrenoceptor compounds [K-i values in nM: (+)niguldipine (0.04-1 .2) and SNAP 5399 xy)methyl-5-carboxamido-6-ethyl-4-(4-nitrophenyl)- e ridin-1-yl)propyl)carboxamido-1,4-dihydropyridine hydrate (0.5-4.8)]. The results were consistent with the selective binding of [I-125]L-762 ,459 to the alpha(1A)-adrenoceptor. The specific labeling of the a,, a drenoceptor subtype by [I-125]L-762,459 may make it a useful tool to l ocalize the distribution of the alpha(1A)-adrenoceptor. (C) 1998 Elsev ier Science B.V. All rights reserved.