Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors

Objectives: Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are thereby biomarkers of neuroinflammation. We developed a PET ligand with an aryloxyanilide structure, [O-methyl-C-11]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([C-11]PBR28), to image PBRs. The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey. Methods: Brain (baseline: n=6, blocking: n=1) and whole-body PET imaging (baseline: n=3, blocking: n=1) of [C-11]PBR28 were performed with the measurement of radio metabolite-corrected arterial input function in all brain and two whole body scans. Results: Saturating doses of nonradioactive PBR ligands markedly increased [C-11]PBR28 in plasma (similar to 400% increase) and brain (similar to 200%) at 2 min by displacing radioligand from PBRs in peripheral organs. Brain uptake of radioactivity peaked in baseline scans at similar to 40 min after injection of [C-11]PBR28 and was high (similar to 300% standardized uptake value). The images showed no receptor-free region that could be used for reference tissue analysis. Thus, quantitation of receptor density required measurement of parent radioligand in arterial plasma. Nondisplaceable uptake was estimated from the blocked scans and was only similar to 5% of total distribution volume measured under baseline conditions. Distribution volume of [C-11]PBR28 was stably determined within 110 min of scanning. Conclusions: Regional brain uptake of [C-11]PBR28 in monkey could be quantified as a value proportional to the density of receptors-namely, as equilibrium distribution volume. [C-11]PBR28 had high levels of specific binding in brain and should provide a sensitive measure of changes in PBRs. Published by Elsevier Inc.