PET imaging of MRP1 function in the living brain: method development and future perspectives.

Multidrug resistance-associated protein 1 (MRP1) functions as a primary active transporter utilizing energy from ATP hydrolysis. In the central nervous system (CNS), MRP1 plays an important role in limiting the permeation of xenobiotic and endogenous substrates across the blood-brain and blood-cerebrospinal fluid barriers, and across brain parenchymal cells. While MRP1 contributes to minimizing the neurotoxic effects of drugs, it may also restrict the distribution of drugs for the treatment of CNS diseases. Moreover, neurodegenerative disease may be associated with abnormal expression of efflux transporters in the brain. Noninvasive measurement of MRP1 function will therefore be useful for directly evaluating the effect of modulators on enhancing the penetration of drugs into the brain and for examining the pathophysiological role of MRP1 in the brain. Positron emission tomography (PET) is a powerful molecular imaging technique. While several PET probes have been proposed for imaging function of the efflux transporter P-glycoprotein, few reports discuss the probes for imaging MRP1 function in the brain. Ideally, brain radioactivity should consist of a single radioactive compound that is selectively transported by the efflux transporter of interest, without other efflux routes. However, most PET probes for MRP1 or P-glycoprotein are eliminated by both a transporter and simple diffusion, resulting in inaccurate measurement of pump function. This review addresses a new strategy to avoid this problem, and suggests the design of a PET probe based on this strategy, particularly for MRP1 imaging. Several published reports on imaging MRP1 function with PET are also discussed.