Synthesis and evaluation of novel PET probes for P-gp expression and function

Objectives P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the brain against toxic substances. We labeled a modulator (MC266) and inhibitor (MC18) of the pump with ¹¹C, resulting in potential tracers of P-gp function and expression.

Methods MC18, MC266 and verapamil were labeled using ¹¹CH₃I. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA), or cold MC18.

Results Cerebral distribution volumes (DV) of ¹¹C-MC18 (2.4±0.2) and ¹¹C-MC266 (2.0±0.2) in untreated rats were higher than of ¹¹C-verapamil (0.66±0.11). DVs of ¹¹C-MC266 and ¹¹C-verapamil were significantly increased by 50 mg/kg CsA (to 5.2±0.3 and 5.6±0.3, respectively). The DV of ¹¹C-MC18 was reduced by cold MC18 (to 1.7±0.1). Its SUV was also reduced (up to 67%) in several peripheral organs which express P-gp.

Conclusions ¹¹C-MC266 is a novel tracer of Pgp function with higher baseline uptake than ¹¹C-verapamil. Upregulation of P-gp function in response to treatment may be detectable using ¹¹C-MC266 and PET. Since ¹¹C-MC18 shows specific binding in target organs, this compound is a unique tracer of P-gp expression, although a derivative with higher affinity for the pump may be required for quantitative imaging. The prospect of independent assessment of pump function and expression is quite exciting.