First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues

• Published in: European journal of nuclear medicine and molecular imaging Vol. 51; no. 13; pp. 3900 - 3911
• Main Authors: Mairinger, Severin, Jackwerth, Matthias, Chalampalakis, Zacharias, Rausch, Ivo, Weber, Maria, Wölfl-Duchek, Michael, Pracher, Lena, Nics, Lukas, Pahnke, Jens, Langsteger, Werner, Hacker, Marcus, Zeitlinger, Markus, Langer, Oliver
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2024; Springer Nature B.V
• Subjects: Adult; Cardiology; Cerebellum; Cerebral cortex; Choroid plexus; Computed tomography; Dosimeters; Dosimetry; Drug resistance; Female; Human tissues; Humans; Imaging; Kidneys; Liver; Lungs; Male; Material requirements planning; Medicine; Medicine & Public Health; Men; Middle Aged; MRP protein; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Myocardium; Nuclear Medicine; Oncology; Original; Original Article; Orthopedics; Positron emission; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography - methods; Protein transport; Proteins; Radiation; Radiation dosage; Radioactive Tracers; Radiology; Radiopharmaceuticals - pharmacokinetics; Respiratory diseases; Retina; Sex differences; Tissue Distribution; Women; MRP1; Multidrug resistance-associated proteins; C]methylpurine; Dosimetry; Long axial field-of-view PET/CT; Test-retest variability; 6-Bromo-7-; 6-Bromo-7-[11C]methylpurine
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-024-06851-2

Purpose 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-[ 11 C]methylpurine ([ 11 C]BMP) has been used to measure MRP1 function in rodents. In this study, [ 11 C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. Methods 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 [ 11 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 E , h − 1 ) 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. Results Mean k E and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h − 1 (− 4 ± 24%), cerebellum: 0.033 ± 0.009 h − 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h − 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h − 1 (30 ± 38%), lungs: 0.875 ± 0.095 h − 1 (− 3 ± 11%), myocardium: 0.641 ± 0.105 h − 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h − 1 (14 ± 16%), and liver: 0.685 ± 0.072 h − 1 (7 ± 9%). Significant sex differences were found for k E 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. Conclusion LAFOV PET/CT with [ 11 C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of k E in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [ 11 C]BMP was in the typical range of 11 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. Trial registration EudraCT 2021-006348-29. Registered 15 December 2021.