Evaluation of [18F]-(-)-norchlorofluorohomoepibatidine ([18F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates

Abstract

IntroductionThe aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4β2 receptor radiotracer [18F]-(-)-NCFHEB ([18F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. Methods[18F]-(-)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24mg/kg). Radiometabolites in plasma were measured using HPLC. Results[18F]-(-)-NCFHEB was prepared in a total synthesis time of 140min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3±16.1GBq/μmol (n=6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98-100% of [18F]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9±1.0mL/cm3 (n=2), or 6.6±1.1mL/cm3 after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [18F]-(-)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus=4.1±1.5, frontal cortex=1.2±0.2, putamen=0.96±0.45, and cerebellum=0.10±0.29). ConclusionAn efficient microfluidic synthetic method was developed for preparation of [18F]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [18F]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4β2 receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [18F]2-FA and comparable to [18F]AZAN. These results confirm previous findings and support further examination of [18F]-(-)-NCFHEB in humans.