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 (11)C-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 (11)C-TMSX (adenosine A(2A) receptor), (11)C-MPDX (adenosine A(1) receptor), (11)C-PK11195 (peripheral benzodiazepine receptor), (11)C-flumazenil (central benzodiazepine receptor), (11)C-raclopride (dopamine D(2)-like receptor), (11)C-pyrilamine (histamine H(1) receptor), (11)C-PIB (amyloid plaque), and (11)C-donepezil (acetylcholine esterase).


RESULTS
In assay 1, CsA treatment increased both the uptake and the brain-to-blood ratio of (11)C-TMSX, (11)C-MPDX, (11)C-flumazenil, and (11)C-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 (11)C-verapamil, but TMSX, MPDX, and MPPF did not increase either parameter.


CONCLUSIONS
Assay 1 was suitable for evaluating the P-gp modulation of radioligands. Among the 8 radioligands investigated, (11)C-TMSX, (11)C-MPDX, (11)C-flumazenil, and (11)C-donepezil were modulated by P-gp.
Ishiwata
Kiichi
K
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. ishiwata@pet.tmig.or.jp
Kawamura
Kazunori
K
Yanai
Kazuhiko
K
Hendrikse
N Harry
NH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D000077265:Donepezil; D005442:Flumazenil / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D011984:Sensory Receptor Cells / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C451639:1-methyl-8-dicyclopropylmethyl-1-methyl-3-propylxanthine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007189:Indans; C405422:KF18446; D008024:Ligands; D010880:Piperidines; D011868:Radioisotopes; D014970:Xanthines; D005442:Flumazenil; D016572:Cyclosporine; D000077265:Donepezil; D014700:Verapamil