Development and optimization of a novel automated loop method for production of [11C]nicotine.

A novel, rapid, and automated loop method for the synthesis of [11C]nicotine was developed and optimized. The method involves, a reaction of the precursor, (+) nornicotine or (-) nornicotine, with a gas-phase produced [11C]CH3I in an 800 µL loop at 75 °C for 5 min followed by a semi-preparatory Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) purification. The optimized synthesis and purification process was complete in < 30 min and produced [11C]nicotine with > 99.9% Radiochemical Purity (RCP), no [11C]CH3I, no (+) nornicotine, 105 mCi/µmole specific activity, 7.0 - 7.2 pH, and 16.6% ethanol. The current method can be optimized, to reduce the ethanol content (<10%), and can be translated to a cGMP production of [11C]nicotine for human clinical trials.

A programmable smoke delivery device for PET imaging with cigarettes containing 11C-nicotine.

INTRODUCTION: PET imaging with 11C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. NEW METHOD: The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11C-nicotine-loaded cigarette. RESULTS: Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. COMPARISON WITH EXISTING METHODS: This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. CONCLUSIONS: The SDD is effective in delivering 11C-nicotine from the study cigarettes. Despite a 2-s increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke.

Biodistribution and Radiation Dosimetry of 11C-Nicotine from Whole-Body PET Imaging in Humans.

This study assessed the in vivo distribution of 11C-nicotine and the absorbed radiation dose from whole-body 11C-nicotine PET imaging of 11 healthy (5 male and 6 female) subjects. Methods: After an initial CT attenuation scan, 11C-nicotine was administered via intravenous injection. A dynamic PET scan was acquired for 90 s with the brain in the field of view, followed by a series of 13 whole-body PET scans acquired over a 90-min period. Regions of interest were drawn over organs visible in the reconstructed PET images. Time-activity curves were generated, and the residence times were calculated. The absorbed radiation dose for the whole body was calculated by entering the residence time in OLINDA/EXM 1.0 software to model the equivalent organ dose and the effective dose for a 70-kg man. Results: The mean residence times for 11C-nicotine in the liver, red marrow, brain, and lungs were 0.048 ± 0.010, 0.031 ± 0.005, 0.021 ± 0.004, and 0.020 ± 0.005 h, respectively. The mean effective dose for 11C-nicotine was 5.44 ± 0.67 µSv/MBq. The organs receiving the highest absorbed dose from the 11C-nicotine injection were the urinary bladder wall (14.68 ± 8.70 µSv/MBq), kidneys (9.56 ± 2.46 µSv/MBq), liver (8.94 ± 1.67 µSv/MBq), and spleen (9.49 ± 3.89 µSv/MBq). The renal and hepatobiliary systems were the major clearance and excretion routes for radioactivity. Conclusion: The estimated radiation dose from 11C-nicotine administration is relatively modest and would allow for multiple PET examinations on the same subject.

A mild, rapid synthesis of freebase [11C]nicotine from [11C]methyl triflate.

A rapid, mild radiosynthesis of freebase [11C]nicotine was developed by the methylation of freebase nornicotine with [11C]methyl triflate in acetone (5min, 45°C). A basic (pH 10.5-11.0) HPLC system reproducibly yielded freebase [11C]nicotine as a well-defined single peak. The freebase [11C]nicotine was concentrated by solid phase extraction and formulated in 50µL ethanol (370MBq/50µL) without evaporative loss suitable for a cigarette spiking study. A radiochemical yield of 60.4±4.7% (n=3), radiochemical purity ≥99.9% and specific activity of 648GBq/µmol at EOB for 5min beams were achieved.