In vivo evaluation of P-glycoprotein modulation of 8 PET radioligands used clinically

P-glycoprotein (P-gp) regulates the ability of endogenous and exogenous compounds to cross the blood-brain barrier. We investigated whether PET tracers used clinically for studying brain function are affected by P-gp. Methods: Modulation of 8 radioligands by P-gp was assayed in mice by evaluating the effect of treatment with cyclosporine A (CsA) on uptake into the brain (assay 1) and the effect of treatment with a cold ligand of the corresponding radioligand on uptake of ¹¹C-verapamil, a representative radioligand for P-gp (assay 2). Brain-to-blood ratios were also examined as the other index to correct the delivery of radioligands. The radioligands investigated were ¹¹C-TMSX (adenosine A_2A receptor), ¹¹C-MPDX (adenosine A₁ receptor), ¹¹C-PK11195 (peripheral benzodiazepine receptor), ¹¹C-flumazenil (central benzodiazepine receptor), ¹¹C-raclopride (dopamine D₂-like receptor), ¹¹C-pyrilamine (histamine H₁ receptor), ¹¹C-PIB (amyloid plaque), and ¹¹C-donepezil (acetylcholine esterase). Results: In assay 1, CsA treatment increased both the uptake and the brain-to-blood ratio of ¹¹C-TMSX, ¹¹C-MPDX, ¹¹C-flumazenil, and ¹¹C-donepezil among the 8 radioligands. In assay 2, in which 4 cold ligands were examined, cold verapamil slightly increased the brain-to-blood ratio of ¹¹C-verapamil, but TMSX, MPDX, and MPPF did not increase either parameter. Conclusion: Assay 1 was suitable for evaluating the P-gp modulation of radioligands. Among the 8 radioligands investigated, ¹¹C-TMSX, ¹¹C-MPDX, ¹¹C-flumazenil, and ¹¹C-donepezil were modulated by P-gp.