PROGESTIN RADIOPHARMACEUTICALS LABELED WITH TECHNETIUM AND RHENIUM - SYNTHESIS, BINDING-AFFINITY, AND IN-VIVO DISTRIBUTION OF A NEW PROGESTIN N2S2-METAL CONJUGATE

We have prepared and evaluated three metal conjugates of a progestin-m onoamine-monoamide (MAMA') bisthiol chelate system. These conjugates o f rhenium and technetium-99 and -99m, are structural analogs of the bi samino-bisthiol (BAT) conjugates we have described recently, but the M AMA' chelate, being more polar than the BAT system, gives a conjugate that is much less lipophilic, having an octanol-water partition coeffi cient that is nearly 80-fold lower. In competitive binding assays, the Re- and Tc-99m-MAMA'-progestin conjugates bind to the progesterone re ceptor with affinities greater than that of progesterone itself, and i n a direct binding assay, the equilibrium dissociation constant (K(d)) of the Tc-99m-MAMA' conjugate was 0.97 nM. As is typical for 11beta-s ubstituted progestins, these conjugates also have substantial binding affinity for glucocorticoid receptors. In tissue distribution studies in immature female rats, the progestin-Tc-99m-MAMA' conjugates show se lective uptake for principal target tissue (such as uterus) over that of blood and nontarget tissue (such as muscle); these uptake ratios re ach maximum levels of 5 and 4, respectively. Uptake by fat, liver, and kidney is quite high; however, only the uptake in uterus is displacea ble upon coinjection of the selective progestin ORG2058. Metabolism st udies show that the radioactivity in the uterus is essentially unmetab olized out to 4 h, while liver activity is completely due to metabolit es. Other tissues show an intermediate fraction of unmetabolized conju gates that decreases with time. The in vivo behavior of the progestin- Tc-99m-MAMA' conjugate is similar to that of the labeled BAT conjugate : its uptake selectivity is somewhat greater than that of the BAT conj ugate, but its target tissue uptake is lower. Factors that may be resp onsible for limiting the target tissue uptake properties of these conj ugates are their moderate affinity for progesterone receptor, their su bstantial binding to glucorticoid receptors, and their large overall m olecular size.