Fluoro-, bromo-, and iodopaclitaxel derivatives: synthesis and biological evaluation

Paclitaxel (Taxol[reg]) is a clinically important chemotherapeutic agent. We describe the synthesis of fluoro-, bromo-, and iodopaclitaxel and their [18F]fluoro-, [76Br]bromo-, and [124I]iodo- analogues. [18F]Fluoropaclitaxel shows high uptake and rapid clearance from tissues in rats. Preadministration of paclitaxel in normal rats significantly increases (p < 0.005) retention of [18F]fluoropaclitaxel and [76Br]bromopaclitaxel in blood (33.0%), heart (32.0%), lung (37.6%) kidney (142.4%); and blood (33.4%), lung (42.3%), kidney (62.4%), respectively. [18F]Fluoropaclitaxel uptake in the brain of mdr1a/1b(-/-) mice is increased 1400% (p < 1.3e-07) relative to wild-type controls. Preadministration of paclitaxel or XR9576, a modulator, had little effect on the biodistribution in these mdr1a/1b(-/-) mice. As a result, [18F]fluoropaclitaxel will be a useful radiopharmaceutical for the study of multidrug resistant tumors