Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET.

XR9576 (tariquidar) is an anthranilic acid derivative and potent P-glycoprotein (P-gp) inhibitor. XR9576 has undergone phase I and II studies as combined chemotherapy against cancer. XR9576 has been developed as a useful therapeutic agent but not as a PET probe. We therefore developed [¹¹C]XR9576 as a PET probe and assessed whether PET studies using [¹¹C]XR9576 are a promising approach to assess P-gp function primarily. We synthesized [¹¹C]XR9576 by methylation of 7- O-desmethyl XR9576 with [¹¹C]methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [¹¹C]XR9576 in mice were investigated. PET studies using [¹¹C]XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [¹¹C]XR9576 were measured in the brain and plasma of mice. [¹¹C]XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [¹¹C]XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUC_{brain [0–60 min]} in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [¹¹C]XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [¹¹C]XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUC_brain of [¹¹C]XR9576 correlates with P-gp and Bcrp functions. PET studies using [¹¹C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors. [ABSTRACT FROM AUTHOR]