Biodistribution and kinetics of radiolabelled pyrrolidino-4-iodo-tamoxifen: prospects for pharmacokinetic studies using PET.

With a view to evaluating the role of PET imaging in early clinical studies of new anticancer drugs, we are investigating the recently developed antiestrogen compound pyrrolidino-4-iodo-tamoxifen (idoxifene). Preliminary experimental studies have been undertaken using [125,131I]idoxifene, following synthesis of a tributyl-stannyl-idoxifene precursor to facilitate radioiodination. We have investigated the tissue biodistribution and kinetics of [125I]idoxifene following i.v. infusion in hooded rats bearing the hormone-dependent transplantable mammary tumour OES.HR1. Clearance of idoxifene from the circulation is accompanied by an increase in uptake by tumour and uterus, to peak levels after 24 hours (0.33 +/- 0.037% dose/g (mean +/- 1 SD) and 0.40 +/- 0.033% dose/g, respectively). Highest uptake of idoxifene was found in the liver (11.0 +/- 0.8% dose/g), with a progressive fall after 24 hours consistent with hepatobiliary excretion of the radiotracer. No evidence of idoxifene metabolism was found in tissue extracts taken up to 48 hours. Whole body clearance of [131I]idoxifene was characterised by a single exponential decay (t1/2 = 140 hours) up to 350 hours post administration. We conclude that 124I-labelled idoxifene combined with PET imaging would facilitate human in vivo pharmacokinetic studies of this new anticancer drug and provide an opportunity to investigate relationships between drug uptake and tumour response.