(−)‐[¹⁸F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use

Abstract

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 β2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (-)-[(18) F]flubatine, which was purified by semi-preparative HPLC. (-)-[(18) F]Flubatine was prepared in 25% radiochemical yield (formulated for clinical use at end of synthesis, n = 3), >95% radiochemical purity, and specific activity = 4647 Ci/mmol (171.9 GBq/µmol). Doses met all quality control criteria confirming their suitability for clinical use. Evaluation of (-)-[(18) F]flubatine in rhesus macaques was performed with a Concorde MicroPET P4 scanner (Concorde MicroSystems, Knoxville, TN). The brain was imaged for 90 min, and data were reconstructed using the 3-D maximum a posteriori algorithm. Image analysis revealed higher uptake and slower washout in the thalamus than those in other areas of the brain and peak uptake at 45 min. Injection of 2.5 µg/kg of nifene at 60 min initiated a slow washout of [(18) F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min.

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

“…47 This tracer was demonstrated to detect differences in synaptic acetylcholine concentration induced by receptor inhibitors in Rhesus monkeys. 48 The first fully automated radiosynthesis of this compound validated for human use 49 was reported in 2013 and first-in-human results of administration of the radiotracer showed no adverse effects in humans. 50 Tracer binding to plasma proteins in human blood was demonstrated in vitro and ex vivo to show no differences between patients with Alzheimer’s disease and healthy controls.…”

Radiosyntheses using Fluorine-18: The Art and Science of Late Stage Fluorination

“…However, due to low radiochemical yields, other candidate precursors were explored for radiolabeling and the BOC-protected trimethylammonium iodide precursor (BOC-trimethylammoniumhomo-epibatidine, BTHEB) was shown to give the best yields of approximately 60% and adapted for fully automated synthesis [135]. This precursor has since become commercially available, making it more accessible for clinicians, and a validated production method suitable for clinical application has been reported by our group (Scheme 21b) [139]. …”

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…The radiosynthesis was independent of the use of a microwave and was easily transferable to automated synthesis modules to prepare for human application. Recently, automated synthesis has been reported by two institutions with RCYs of 30% [165] and 25% [166] .…”

“…The radiosynthesis was independent of the use of a microwave and was easily transferable to automated synthesis modules to prepare for human application. Recently, automated synthesis has been reported by two institutions with RCYs of 30% [165] and 25% [166] .The above-mentioned electron withdrawing groups (-I effect, -M effect) bound to aromatic moieties are a definite need to enable a nucleophilic attack. In a recent study on radiolabeling of cannabinoid receptor type 2-selective compounds (Fig.…”