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

Introduction: The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine alpha(4)beta(2) receptor radiotracer [F-18]-(-)-NCFHEB ([F-18]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. Methods: [F-18]-(-)-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 (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. Results: [F-18]-(-)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 +/- 16.1 GBq/mu mol (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 [F-18]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume (V-ND) was estimated at 5.9 +/- 1.0 mL/cm(3) (n = 2), or 6.6 +/- 1.1 mL/cm(3) after normalization by the plasma free fraction f(p). 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, [F-18]-(-)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 +/- 1.5, frontal cortex = 12 +/- 0.2, putamen = 0.96 +/- 0.45, and cerebellum = 0.10 +/- 029). Conclusion: An efficient microfluidic synthetic method was developed for preparation of [F-18]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [F-18]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of alpha(4)beta(2) receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [18F]2-FA and comparable to [F-18]AZAN. These results confirm previous findings and support further examination of F-18]-(-)-NCFHEB in humans. (C) 2015 Elsevier Inc. All rights reserved.