Characterization of specific binding of L-762,459, a selective α1A-adrenoceptor radioligand to rat and human tissues

Abstract L-762,459 ((±)1-(3-{[5-carbamoyl-2-{2-[(4-hydroxy-3-iodobenzimidoyl)-amino]-ethoxy-methyl}-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]-amino}-propyl)-4-phenyl-1-piperidine-4-carboxylic acid methyl ester), an analog of a series of dihydropyridines previously reported to be selective α 1A -adrenoceptor subtype antagonists was found to have α 1A -adrenoceptor subtype selectivity ( K i (nM), 1a=1.3, 1b=240, 1d=280). Specific [ 125 I ] L-762,459 binding was detected in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the α 1A -adrenoceptor subtype, but not in tissues known to contain α 1B -adrenoceptor (spleen, liver) and α 1D -adrenoceptor (aorta). Scatchard analysis of [ 125 I ] L-762,459 binding in rat cerebral cortex and prostate indicated a single 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 [ 125 I ] 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-selective α 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 α 1A -adrenoceptor compounds [ K i values in nM: (+) niguldipine (0.04–1.2) and SNAP 5399 ((±)-2-((2-aminoethyl)oxy)methyl-5-carboxamido-6-ethyl-4-(4-nitrophenyl)-3- N -(3-(4,4-diphenylpiperidin-1-yl)propyl)carboxamido-1,4-dihydropyridine hydrate (0.5–4.8)]. The results were consistent with the selective binding of [ 125 I ] L-762,459 to the α 1A -adrenoceptor. The specific labeling of the α 1A -adrenoceptor subtype by [ 125 I ] L-762,459 may make it a useful tool to localize the distribution of the α 1A -adrenoceptor.