Advancing 6-bromo-7-[ 11 C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates.

Autor: Mairinger S; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. severin.mairinger@meduniwien.ac.at.; Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria. severin.mairinger@meduniwien.ac.at., Jackwerth M; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria., Soukup O; Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic., Blaickner M; Department Computer Science, University of Applied Sciences Technikum Wien, Vienna, Austria., Decristoforo C; Department of Nuclear Medicine, Medical University Innsbruck, Innsbruck, Austria., Nics L; Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria., Pahnke J; Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo, Oslo, Norway.; Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital, Oslo, Norway.; Institute of Nutritional Medicine (INUM) and Lübeck Institute of Dermatology (LIED), University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany.; Department of Pharmacology, Faculty of Medicine, University of Latvia, Rīga, Latvia.; School of Neurobiology, Biochemistry and Biophysics, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel., Hacker M; Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria., Zeitlinger M; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria., Langer O; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.; Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
Jazyk: angličtina
Zdroj: EJNMMI radiopharmacy and chemistry [EJNMMI Radiopharm Chem] 2024 Apr 29; Vol. 9 (1), pp. 34. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1186/s41181-024-00265-z
Abstrakt: Background: 6-Bromo-7-[ 11 C]methylpurine ([ 11 C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [ 11 C]BMP afforded a mixture of 7- and 9-[ 11 C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [ 11 C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data.
Results: [ 11 C]BMP was synthesised by regioselective N 7 -methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [ 11 C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [ 11 C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [ 11 C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [ 11 C]BMP will deliver an effective dose in the typical range of 11 C-labelled radiotracers.
Conclusions: [ 11 C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [ 11 C]BMP will be safe and well tolerated in humans.
(© 2024. The Author(s).)
Databáze: MEDLINE
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