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Abstract Background 6-Bromo-7-[11C]methylpurine ([11C]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 [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. Results [11C]BMP was synthesised by regioselective N 7 -methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]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 [11C]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 [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. Conclusions [11C]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 [11C]BMP will be safe and well tolerated in humans.

Abstract Background [11C]Metoclopramide is a new radiotracer for investigating the activity of P-glycoprotein at the blood-brain barrier. A highly stable and reproducible radiosynthesis is a prerequisite for clinical studies applying [11C]metoclopramide or other 11C-labelled radiotracers, therefore all potential pitfalls must be identified and monitored to allow a stable process. Results Long-term production (n = 94 in a time range of approximately 2 years) of [11C]metoclopramide synthesized on two commercially available synthesizers yielded 3.9 ± 2.0 GBq of product with a molar activity of 132 ± 164 GBq/μmol and an overall success rate of 93%. During all successful productions, the product quality was in accordance with the recommendations of the European Pharmacopoeia. The most common pitfalls that were identified for the radiosynthesis included poor turnover into [11C]CH3OTf, decomposition of the solvent or insufficient semi-preparative HPLC performance. Conclusion The study provides long-term insight in the improved, robust and stable preparation of [11C]metoclopramide for human use.

Abstract Background [11C]erlotinib has been proposed as a PET tracer to visualize the mutational status of the epidermal growth factor receptor (EGFR) in cancer patients. For clinical use, a stable, reproducible and high-yielding radiosynthesis method is a prerequisite. In this work, two production schemes for [11C]erlotinib applied in a set of preclinical and clinical studies, starting from either [11C]CH4 or [11C]CO2, are presented and compared in terms of radiochemical yields, molar activities and overall synthesis time. In addition, a time-efficient RP-HPLC method for quality control is presented, which requires not more than 1 min. Results [11C]erlotinib was reliably produced applying both methods with decay-corrected radiochemical yields of 13.4 ± 6.2% and 16.1 ± 4.9% starting from in-target produced [11C]CO2 and [11C]CH4, respectively. Irradiation time for the production of [11C]CO2 was higher in order to afford final product amounts sufficient for patient application. Overall synthesis time was comparable, mostly attributable to adaptions in the semi-preparative HPLC protocol. Molar activities were 1.8-fold higher for the method starting from [11C]CH4 (157 ± 68 versus 88 ± 57 GBq/μmol at the end of synthesis). Conclusions This study compared two synthetic protocols for the production of [11C]erlotinib with in-target produced [11C]CO2 or [11C]CH4. Both methods reliably yielded sufficiently high product amounts for preclinical and clinical use.