Synthesis and Preclinical Evaluation of Novel PET Probes for P-Glycoprotein Function and Expression

P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with C-11, resulting in potential tracers of P-gp function and expression. Methods: 6 and 7 were labeled using (CH3I)-C-11. C-11-verapamil was prepared as published previously, using C-11-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). Results: The radiochemical yields of C-11-6 and C-11-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of C-11-6 (2,35 +/- 0.11) and C-11-7 (1.86 +/- 0.15) in saline-treated rats were higher than or C-11-verapamil (0.64 +/- 0.12). DVs of C-11-7 and C-11-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of C-11-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. Conclusions: C-11-7 is a novel tracer of P-gp function with higher baseline uptake than C-11-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with C-11-verapamil) may be detectable using C-11-7 and PET. Because C-11-6 shows specific binding in target organs, this compound is the First PET tracer allowing measurement of P-gp expression.