Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET

Experience with imaging of the multi-drug resistance (MDR) phenotype in rum ours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp ) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are require d. One approach to these problems is the development of short half-lift pos itron-emitting tracers which are substrates of Pgp. Several lipophilic cati onic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purification steps. The chemistry is suitable fur use with very short half-lift: radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to suppor t clinical imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is signi ficantly reduced after several months of conditioning in the presence of do xorubicin, which induces increased Pgp expression. Uptake in hooded rat sar coma (HSN) cells, which express Pgp, is significantly increased in the pres ence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumour -bearing rats showed uptake in tumour increasing up to 30 min p.i. while it was decreasing in other tissues. for development of radiopharmaceuticals c ontaining copper radionuclides, and that this series of complexes should un dergo further evaluation in vivo as position emission tomography imaging ag ents fur MDR.