Synthesis of the 7alpha-cyano-(17alpha,20E/Z)-[125I]iodovinyl-19-nortestosterones: potential radioligands for androgen and progesterone receptors.
We report the preparation of the 7alpha-cyano derivative of the isomeric (17alpha,20E/Z)-[125I]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 7alpha-position by hydrocyanation of 4,6-estradien-17beta-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 7alpha-cyano-17alpha-ethynyl-19-nortestosterone. The stannyl derivatives were prepared by addition of tri-n-butylstannyl hydride and converted stereospecifically to the corresponding [125I]iodovinyl analog using [125I]NaI and H2O2. The [125I]iodovinylsteroids were intravenously administered to male rats and estrogen-primed immature female rats and tissue uptake was measured up to 6h 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 125I-ligands. However co-injection of testosterone to DES-primed male rats induced a marked increase in prostate uptake of the 20Z-isomer of 7alpha-cyano-[125I]-IVNT. The relative binding affinity (RBA) of either 7alpha-cyano-(17alpha,20E/Z)-IVNT isomer for the AR is low (RBA=4 and 3, respectively, versus 100 for 5alpha-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 7alpha-methyl-[125I]-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 7alpha-cyano group to 123I-labeled nortestosterone derivatives does not improve their potential to serve as SPECT agents for the imaging of AR densities in the prostate.
Ali
Hasrat
H
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Que., Canada J1H 5N4.
Rousseau
Jacques
J
Ahmed
Naseem
N
Guertin
Veronique
V
Hochberg
Richard B
RB
van Lier
Johan E
JE
D000728:Androgens / Q000138:chemical synthesis* / Q000378:metabolism*; D000818:Animals; D005260:Female; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D011467:Prostate / Q000000981:diagnostic imaging*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014599:Uterus / Q000000981:diagnostic imaging / Q000378:metabolism
D000728:Androgens; D007457:Iodine Radioisotopes; D008024:Ligands; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D009277:Nandrolone