Synthesis and target tissue uptake of the 20Z and 20E isomers of 17α‐[¹²⁵I]iodovinylestradiol

Abstract

A number of halogenated estrogens have been prepared over the past years as possible radiopharmaceuticals for receptor imaging in conjunction with the management of breast cancer. Among them the (1 71~,20E)-[~~~1]iodovinyl derivatives of estradiol (1-3) and llp-methoxyestradiol (2.4) showed the required in vivo and in vitro properties of a high-affinity estrogen-receptor radiopharmaceutical (1.4.5). The procedures used for the syntheses of these 171~-iodovinylestrogens result mainly in the formation of the 20E isomers. and accordingly only the chemistry and biological properties of the latter isomers have been reported (1-5). In the case of the analogous 171~-iodovinylnortestosterone, syntheses of both the 20E and 202 isomers have been reported (6.7) and, furthermore, the 202 isomer was found to exhibit the more interesting biological properties (7.8). On such accounts we prepared both the 20E and 202 isomers of 171~-[~~~1]iodovinylestradiol, as well as the nonradiolabeled analogs, and compared their in vitro and in vivo properties. Among the two isomers, the 202 isomer 6 exhibited the highest receptor-mediated target tissue uptake. 4 1 HO HO 6 5 3For the introduction of the iodine, or radioiodine, onto the vinyl substituent we used the destannylation method. This rapid, electrophylic substitution reaction has previously been used for the preparation of the (I 71~,20E)-iodovinylestradiol 3 and was shown to be stereospecific resulting in good yield and high specific activities of the desired radiopharmaceutical (1.4). To obtain both the 20E and 202 precursor of 3 and 6. e.g. the (1 7a,20E)or (1 7a.202)-tributylstannylvinylestradiol 2 or 4, we adapted the procedures described for the analogous nortestosterone derivatives (6.7). Treatment for 4 h of 171~-ethynylestradiol I with tri-n-butyltin hydride in toluene at 90-100 O C , in the presence of azobisisobutyronitrile as a catalyst, gave the 20E isomer 2 as a major product in 75% yield. The same reaction in hexamethylphosphorictriamide. e.g. a polar solvent, at 65-70 OC gave mixtures of the 202 and 20E isomers 2 and 4. with the 202 isomer 4 as the major product, together the 17a-vinyl derivative 5 and unreacted starting material. The ratio between the 2 and E isomers was found to depend on the temperature, with higher temperatures favoring formation of

Steroid reactions and partial synthesis

“…A photochemical double-ring contraction with the extrusion of carbon monoxide has been observeda9 in the conversion of 4ahomo-5a-cholest-3-en-l-one (96) to the cyclobutane (97). The J Product (89) -$p H (97) photosensitized oxidation of the enol of the ring A diketone (98) has been shown to affordg0 the lactol (99). Studies on the photochemical reactivity of the methyl ether of 8,9-didehydroestrone towards singlet oxygen have been reported.g1 The photochemical radical fragmentation of the hemi-acetal (1 00) in the presence of diacetoxyiodobenzene has providedg2 a convenient synthesis of medium-sized lactones ( 101) and (102).…”