Effect of probenecid on the whole-body disposition of 6-bromo-7-[11C]methylpurine in humans assessed with long axial field-of-view PET/CT.

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Multidrug resistance-associated proteins (MRPs) have a widespread tissue distribution. They play an important role in drug disposition and drug-drug interactions (DDIs) and have been associated with various diseases. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to assess MRP1 function in the brain and lungs of mice. [11C]BMP crosses cellular membranes by passive diffusion followed by intracellular conjugation with glutathione and MRP1-mediated efflux of the radiolabelled glutathione-conjugate. In this study, we assessed the effect of the prototypical organic anion transporter inhibitor probenecid on the whole-body disposition of [11C]BMP to examine its suitability for measuring the function of MRP1 and possibly other MRP subtypes across multiple tissues. Seven healthy volunteers (3 women, 4 men) underwent two dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP, without and with pre-treatment with a single oral dose of probenecid. Volumes of interest were outlined for several MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, skeletal muscle, kidneys, and liver). Tissue time-activity curves were corrected for the contribution of vascular radioactivity and the elimination rate constant (kE, h- 1) was calculated as a parameter for tissue MRP function. Radioactivity was primarily excreted into the urinary bladder and urinary clearance was significantly decreased after probenecid administration (- 50 ± 16%). Following probenecid administration, kE was significantly decreased in the kidneys (- 43 ± 20%), liver (- 18 ± 15%), myocardium (- 16 ± 12%), skeletal muscle (- 51 ± 34%), and retina (- 57 ± 29%, non-blood-corrected). Our study highlights the great potential of LAFOV PET/CT to assess drug disposition and transporter-mediated DDIs in humans at a whole-body, multi-tissue level. Due to the slow elimination of [11C]BMP-derived radioactivity from the human brain, [11C]BMP appears unsuitable to measure cerebral MRP1 function in humans, but it may be used to assess the function of MRP1 and possibly other MRP subtypes in various peripheral tissues. EudraCT 2021-006348-29. Registered 15 December 2021.