Mossel Pascalle, Salvi de Souza Giordana, Willemsen Antoon T M, Stormezand Gilles N, Colabufo Nicola A, Toyohara Jun, Boersma Hendrikus H, Dierckx Rudi A J O, Lammertsma Adriaan A, Bartels Anna L, Luurtsema Gert
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Eur J Nucl Med Mol Imaging. 2025 May 8. doi: 10.1007/s00259-025-07320-0.
P-glycoprotein (P-gp) or multidrug-resistance protein is one of the most extensively studied efflux transporters at the blood-brain barrier (BBB). Changes in P-gp function are associated with several neurodegenerative and psychiatric diseases, including Alzheimer's disease, Parkinson's disease and schizophrenia and with the bioavailability of several pharmaceuticals in the brain, causing multi-drug resistance or side effects. PET imaging can be used to measure the P-gp function in vivo. This study aims to validate [F]MC225 as specific P-gp PET tracer with the use of cyclosporin as selective P-gp inhibitor.
Fourteen healthy volunteers (age 67 ± 5y) were included. Subjects underwent twice a 60 min dynamic [F]MC225 (200MBq) PET scan with continuous arterial blood sampling and a cerebral T1-weighted MRI as anatomical reference. During the second scan, in five subjects, cyclosporin was administered in a dose of 2.5 mg/kg/hour, starting 30 min prior to the scan, to inhibit the BBB P-gp function. Tissue time-activity curves of preselected brain regions (Hammer's atlas) were fitted to a reversible two-tissue compartment model (2T4k) using the metabolite corrected plasma and uncorrected whole blood curves as input functions.
No significant difference was found in plasma kinetics, plasma curves, plasma-to-whole blood ratio, and the parent fraction of the baseline scans and scans after administration of cyclosporin. Volume of distribution values in whole brain grey matter showed a significant increase (6.18 ± 1.29 to 9.00 ± 1.29 mL·cmp = 0.03) after the administration of cyclosporin.
The outcomes of the current study reflect the potential ability of [F]MC225 to measure cyclosporin induced changes in P-gp function at the human BBB in vivo.
EudraCT 2020-001564-28.
P-糖蛋白（P-gp）或多药耐药蛋白是血脑屏障（BBB）中研究最广泛的外排转运蛋白之一。P-gp功能的变化与多种神经退行性疾病和精神疾病相关，包括阿尔茨海默病、帕金森病和精神分裂症，还与多种药物在脑中的生物利用度有关，可导致多药耐药或副作用。正电子发射断层扫描（PET）成像可用于体内测量P-gp功能。本研究旨在使用环孢素作为选择性P-gp抑制剂，验证[F]MC225作为特异性P-gp PET示踪剂。
纳入14名健康志愿者（年龄67±5岁）。受试者接受两次60分钟的动态[F]MC225（200MBq）PET扫描，同时进行连续动脉血采样，并进行脑部T1加权磁共振成像（MRI）作为解剖学参考。在第二次扫描期间，对5名受试者，在扫描前30分钟开始以2.5mg/kg/小时的剂量给予环孢素，以抑制血脑屏障P-gp功能。使用代谢物校正的血浆曲线和未校正的全血曲线作为输入函数，将预选脑区（哈默图谱）的组织时间-活性曲线拟合到可逆双组织隔室模型（2T4k）。
在血浆动力学、血浆曲线、血浆与全血比值以及基线扫描和给予环孢素后的扫描中，母体分数方面未发现显著差异。给予环孢素后，全脑灰质中的分布容积值显著增加（从6.18±1.29增加到9.00±1.29 mL·cmp，P = 0.03）。
本研究结果反映了[F]MC225在体内测量环孢素诱导的人血脑屏障P-gp功能变化的潜在能力。
欧洲临床试验数据库编号2020-001564-28。
