title: (-)-[(18) F]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.
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Hockley
authors.forename: Megan N
authors.initials: MN
authors.lastname: Stewart
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.forename: Carole
authors.initials: C
authors.lastname: Quesada
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
mesh_terms: D000818:Animals; D057205:Automation, Laboratory; D001549:Benzamides / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005462:Fluorine Radioisotopes / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods*; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C115362:fluoronorchloroepibatidine
keywords: (−)-[18F]NCFHEB; nicotinic acetylcholine receptors; norchloro-fluoro-homoepibatidine; positron emission tomography (PET) imaging