Synthesis of the 7α-cyano-(17α,20 E/ Z)-[ [formula omitted]]iodovinyl-19-nortestosterones: potential radioligands for androgen and progesterone receptors

Abstract

We report the preparation of the 7α-cyano derivative of the isomeric (17α,20 E/ Z)-[ 125 I ]iodovinyl-19-nortestosterones (IVNT) together with their binding affinity for the androgen receptor (AR) and their biodistribution in two different animal models. The cyano group was introduced at the 7α-position by hydrocyanation of 4,6-estradien-17β-ol-3-one with diethylaluminum cyanide. Selective protection of the A-ring enone system as the dienol ether followed by ethynylation and deprotection under base and acid hydrolysis condition gave 7α-cyano-17α-ethynyl-19-nortestosterone. The stannyl derivatives were prepared by addition of tri- n-butylstannyl hydride and converted stereospecifically to the corresponding [ 125 I ]iodovinyl analog using [ 125 I ]NaI and H 2O 2. The [ 125 I ]iodovinylsteroids were intravenously administered to male rats and estrogen-primed immature female rats and tissue uptake was measured up to 6 h post-injection. Co-administration of NLP-004 or ORG-2058, highly selective ligands for the progesterone receptor, to the female rats did not affect uterus uptake of the 125 I -ligands. However co-injection of testosterone to DES-primed male rats induced a marked increase in prostate uptake of the 20 Z-isomer of 7α-cyano-[ 125 I ]-IVNT. The relative binding affinity (RBA) of either 7α-cyano-(17α,20 E/ Z)-IVNT isomer for the AR is low (RBA=4 and 3, respectively, versus 100 for 5α-dihydrotestosterone (DHT)), suggesting the absence of a possible role of the AR in the localization process. These findings contrast previously reported data for the analogous 7α-methyl-[ 125 I ]-IVNT where co-administration of testosterone was shown to result in a 50% drop in prostate uptake. These data indicate that the addition of an electron withdrawing 7α-cyano group to 123 I -labeled nortestosterone derivatives does not improve their potential to serve as SPECT agents for the imaging of AR densities in the prostate.