Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):3900-3911. doi: 10.1007/s00259-024-06851-2. Epub 2024 Jul 26.
Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[C]methylpurine ([C]BMP) has been used to measure MRP1 function in rodents. In this study, [C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues.
Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (k, h) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology.
Mean k and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h (- 4 ± 24%), cerebellum: 0.033 ± 0.009 h (1 ± 39%), choroid plexus: 0.292 ± 0.059 h (0.1 ± 16%), retina: 0.234 ± 0.045 h (30 ± 38%), lungs: 0.875 ± 0.095 h (- 3 ± 11%), myocardium: 0.641 ± 0.105 h (11 ± 25%), kidneys: 1.378 ± 0.266 h (14 ± 16%), and liver: 0.685 ± 0.072 h (7 ± 9%). Significant sex differences were found for k in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women.
LAFOV PET/CT with [C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of k in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [C]BMP was in the typical range of C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans.
EudraCT 2021-006348-29. Registered 15 December 2021.
多药耐药相关蛋白 1（MRP1）是一种具有广泛组织分布的转运蛋白，它与阿尔茨海默病和慢性呼吸道疾病的病理生理学有关。用 6-溴-7-[C]甲基嘌呤([C]BMP)进行 PET 已用于测量啮齿动物的 MRP1 功能。在这项研究中，[C]BMP 首次在人类中进行了特征描述，以评估不同组织中 MRP1 和其他 MRP 亚型的功能。
13 名健康志愿者（7 名男性，6 名女性）在长轴向视野（LAFOV）PET/CT 系统上进行了全身动态 PET 扫描，在静脉注射 [C]BMP 后。每性别各有 3 名志愿者进行第二次扫描以评估可重复性。为表达 MRP 的组织（大脑皮层、小脑、脉络丛、视网膜、肺、心肌、肾脏和肝脏）勾勒出感兴趣的区域。从时间-活性曲线中，得出组织 MRP 功能的消除率常数（k，h）作为参数，并计算其测试-复测变异性（TRTV，%）。使用医学内部辐射剂量（MIRD）方法计算辐射剂量。
平均 k 和相应的 TRTV 值为：大脑皮层：0.055±0.010 h（-4±24%）；小脑：0.033±0.009 h（1±39%）；脉络丛：0.292±0.059 h（0.1±16%）；视网膜：0.234±0.045 h（30±38%）；肺：0.875±0.095 h（-3±11%）；心肌：0.641±0.105 h（11±25%）；肾脏：1.378±0.266 h（14±16%）；肝脏：0.685±0.072 h（7±9%）。在小脑、肺和肾脏中，k 的性别差异有统计学意义。男性的有效剂量为 4.67±0.18 µSv/MBq，女性为 4.55±0.18 µSv/MBq。
LAFOV PET/CT 联合 [C]BMP 有可能同时评估人体多种组织的 MRP 功能。不同组织中 k 的平均 TRTV 在可接受范围内，除了视网膜。[C]BMP 的辐射剂量在 C-示踪剂的典型范围内。LAFOV PET/CT 具有在全身多组织水平上评估与药物处置相关的分子靶标的巨大潜力。
EudraCT 2021-006348-29。2021 年 12 月 15 日注册。
