Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Journal of Nuclear Medicine

Héric Valette¹  Marie-Anne Peyronneau¹  Salvatore Cisternino¹  Wadad Saba¹  Bertrand Kuhnast¹  Nicolas Tournier¹  Michel Bottlaender¹  Sébastien Goutal¹  Jean-Michel Scherrmann¹  Frédéric Dollé¹ 

关键词: P-glycoprotein;    breast cancer resistance protein;    blood–brain barrier;    positron emission tomography;    radiotracers;    ABC proteins;   

DOI  :  10.2967/jnumed.110.079608

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Radiolabeled compounds used for brain imaging with PET must readily cross the blood–brain barrier (BBB) to reach their target. Efflux transporters at the BBBP-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP)could limit their uptake by the brain. Methods: We developed and validated an in vitro model using MDCKII cells transfected with human multidrug resistance (MDR1) or BCRP genes and assessed the transport of selected PET ligands by the concentration equilibrium technique. The tested compounds included befloxatone, (R,S)-CGP-12177, clorgyline, R-(−)-deprenyl, diprenorphine, DPA-714, fallypride, flumazenil, 2-fluoro-A-85380, LBT-999, loperamide, p-MPPF, PE2I, Pittsburgh compound B (PIB), (R,S)-PK11195, raclopride, R-(+)-verapamil, and WAY-100635. The assays were performed using the nonradioactive form of each compound (ultraviolet high-performance liquid chromatography analysis) and, when available, the 18F-labeled analogs (γ-counting). Results: Befloxatone appeared to be transported solely by BCRP. Loperamide, verapamil, and diprenorphine were the only P-gp substrates. Other ligands were transported by neither P-gp nor BCRP. Conclusion: The present method can readily be used to screen new-compound transport by P-gp or BCRP, even before any radiolabeling. Compounds that were previously thought to be transported by P-gp in rodents, such as p-MPPF, WAY-100635, and flumazenil, cannot be considered substrates of human P-gp. The impact of BCRP and P-gp at the BBB on the transport of befloxatone and diprenorphine in vivo remains to be evaluated with PET.

【 授权许可】

Unknown