FLUORINE-18-LABELED PROGESTIN KETALS - SYNTHESIS AND TARGET TISSUE UPTAKE SELECTIVITY OF POTENTIAL IMAGING AGENTS FOR RECEPTOR-POSITIVE BREAST-TUMORS

We have studied two new fluorine-substituted progestins as potential i maging agents for progesterone-receptor-positive human breast tumors. The steroids are 16alpha,17alpha-fluoroacetophenone ketals of 16alpha, 17alpha-dihydroxyprogesterone and 16alpha,17alpha,21-trihydroxy-19-nor progesterone. Synthesis of the latter compound in seven steps from 19- norandrost-4-ene-3,17-dione is reported. Both compounds demonstrate hi gh affinity for the progesterone receptor (PgR) (52.5 and 240%, respec tively, relative to R5020 = 100). The syntheses were adapted to F-18-l abeling with 4'-[F-18]-fluoroacetophenone, prepared from 4'-nitroaceto phenone by nucleophilic substitution with (KF)-F-18/Kryptofix. Conside rable adjustment of reaction conditions was required to effect ketaliz ation using tracer quantities of the ketone. In tissue distribution st udies in estrogen-primed immature female rats, both ketals showed sele ctive uterine uptake, which was blocked by coinjection of a saturating dose of the unlabeled progestin ORG 2058. Additionally, metabolic sta bility of the radiolabel was indicated by the low radioactivity levels seen in bone. Both compounds showed relatively high uptake in fat, in accord with their relative lipophilicities demonstrated by HPLC-deriv ed octanol-water partition coefficients. The selective uterine uptake and metabolic stability of these compounds suggests that this class of PgR ligands might be promising for the selective imaging of receptor- positive tumors if derivatives of reduced lipophilicity can be prepare d.