Objectives

Assesses the effect of probenecid, an organic anion transporter inhibitor, on the whole-body disposition of 6-bromo-7-[11C]methylpurine ([11C]BMP) using long axial field-of-view (LAFOV) PET/CT.
Evaluates the suitability of [11C]BMP for measuring the function of multidrug resistance-associated protein 1 (MRP1) and possibly other MRP subtypes across multiple human tissues.
Demonstrates the potential of LAFOV PET/CT to assess drug disposition and transporter-mediated drug-drug interactions (DDIs) in humans at a whole-body, multi-tissue level.

Methodology

Dynamic whole-body PET scans were performed on a LAFOV PET/CT system after intravenous injection of [11C]BMP, without and with pre-treatment with probenecid.
Volumes of interest (VOIs) were outlined for several MRP-expressing tissues.
Tissue time-activity curves (TACs) were corrected for vascular radioactivity contribution.
The elimination rate constant (kE, h−1) was calculated as a parameter for tissue MRP function.
Urinary clearances of total radioactivity and [11C]MPG were calculated.
Statistical analysis: paired t-test.

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).
The percentage of [11C]MPG in plasma was significantly higher after probenecid administration at all three time points measured (5, 20, and 40 min post-injection).
The urinary clearance of [11C]MPG with respect to the plasma concentration was significantly decreased after probenecid administration (-63±19%).

The study is well-designed and utilizes the advanced LAFOV PET/CT technology to assess the effect of probenecid on [11C]BMP disposition.
The use of kE as a parameter for tissue MRP function is justified based on previous rodent studies, but further validation in humans would be beneficial.
The correction of tissue TACs for vascular radioactivity is crucial and appropriately addressed.
A limitation is the lack of direct measurement of [11C]BMP and [11C]MPG concentrations in tissues. This limits the ability to definitively confirm the proposed mechanism of MRP-mediated transport.
While the study suggests [11C]BMP is unsuitable for measuring MRP1 function in the human brain, further investigation with higher doses of probenecid or more specific MRP1 inhibitors could be considered.
The observed regional differences in brain uptake warrant further mechanistic investigation to confirm the relationship with the glutathione-conjugation system.
The discrepancy between the effects of probenecid on the choroid plexus and retina is intriguing and requires further exploration. The authors could discuss potential explanations, such as differences in MRP subtype expression or the involvement of other transporters.