TITRATION OF THE IN-VIVO UPTAKE OF 16-ALPHA-F-18!FLUOROESTRADIOL BY TARGET TISSUES IN THE RAT - COMPETITION BY TAMOXIFEN, AND IMPLICATIONSFOR QUANTITATING ESTROGEN-RECEPTORS IN-VIVO AND THE USE OF ANIMAL-MODELS IN RECEPTOR-BINDING RADIOPHARMACEUTICAL DEVELOPMENT

We have measured in vivo the uptake of 16alpha-F-18!estradiol (FES) b y target tissues in the immature rat at increasing dose levels (obtain ed by dilution of F-18!FES with unlabeled estradiol). This was done t o examine the binding capacity of target tissues in vivo and to determ ine whether the uptake in receptor-rich tissues was flow limited, as t his has implications concerning the appropriateness of using receptor- rich tissues in experimental animals as models for FES uptake by recep tor-poor breast tumors in humans. We also wanted to establish the dose level of the anti-estrogen tamoxifen required to block target tissue uptake of FES. We found that in untreated rats, specific uptake in the uterus saturated at c. 180 pmol/g, in the ovary at c. 54 pmol/g and i n the muscle at c. 2 pmol/g. At an intermediate dose of tamoxifen (570 mug/kg), uptake saturated at somewhat lower levels, and at a high tam oxifen dose (1710 mug/kg), yet lower specific uptake was evident. In t he FES titrations at low dose levels of FES, both the uterus and the o varies, but not the muscle, showed characteristics of flow-limited upt ake, i.e. the uptake-to-dose ratio reached a maximum level. This flow limitation suggests that only when receptor levels are sufficiently lo w will the FES uptake be related to receptor concentration. While rece ptor-rich tissues such as the rat uterus will show this flow limitatio n, the receptor concentration in most primary and metastatic human bre ast tumors is sufficiently low, so that the uptake should parallel rec eptor content. In in vivo distribution studies, target tissues (or tum ors) with low receptor content will be more fully saturated and ligand more readily displaced. Also, uptake by secondary target tissues (i.e . those with a lower content of estrogen receptor, such as muscle, thy mus and kidney) may be better models for assessing the effectiveness o f new breast tumor imaging agents than uptake by receptor-rich tissues .