(S)- and (R)-[11C]nicotine and the metabolite ()-[11C]cotinine. preparation, metabolite studies and in vivo distribution in the human brain using PET

Halldin, Christer; Någren, Kjell; Swahn, Carl‐Gunnar; Långström, Bengt; Nybäck, Henrík

doi:10.1016/0883-2897(92)90173-v

Cited by 52 publications

(37 citation statements)

References 21 publications

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“…There is controversy as to whether cotinine penetrates the BBB from plasma (Halldin et al, 1992;Riah et al, 1998) or whether the detection of cotinine in brain is solely the result of central nicotine metabolism. Recently, nicotine has been shown to be metabolized in rat brain (Jacob et al, 1997) via CYP2B1 (human homolog CYP2B6), and this process is up-regulated after chronic nicotine exposure (Miksys et al, 2000) (although the amount of nicotine metabolism in brain has not been elucidated).…”

Section: Discussionmentioning

confidence: 99%

“…Literature reports on the ability of cotinine to penetrate the BBB to any significant degree are conflicting (Halldin et al, 1992;Riah et al, 1998). Cotinine has been detected in brain after nicotine exposure (Crooks et al, 1997;Riah et al, 1998), but indirect data suggest that this CNS presence may be the result of central nicotine metabolism by CYP2B1, a monooxygenase enzyme which has been detected in rat brain and shown to be induced by chronic nicotine (Jacob et al, 1997;Miksys et al, 2000).…”

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confidence: 99%

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Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Lockman¹,

McAfee²,

Geldenhuys³

et al. 2005

J Pharmacol Exp Ther

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Blood-brain barrier (BBB) nicotine transfer has been well documented in view of the fact that this alkaloid is a cerebral blood flow marker. However, limited data are available that describe BBB penetration of the major tobacco alkaloids after chronic nicotine exposure. This question needs to be addressed, given long-term nicotine exposure alters both BBB function and morphology. In contrast to nicotine, it has been reported that cotinine (the major nicotine metabolite) does not penetrate the BBB, yet cotinine brain distribution has been well documented after nicotine exposure. Surprisingly, therefore, the literature indirectly suggests that central nervous system cotinine distribution occurs secondarily to nicotine brain metabolism. The aims of the current report are to define BBB transfer of nicotine and cotinine in naive and nicotine-exposed animals. Using an in situ brain perfusion model, we assessed the BBB uptake of 3 H]cotinine BBB transfer is not altered by chronic nicotine exposure. To our knowledge, this is the first report detailing the uptake of nicotine and cotinine after chronic nicotine exposure and quantifying the rate of BBB penetration by cotinine.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Lockman¹,

McAfee²,

Geldenhuys³

et al. 2005

J Pharmacol Exp Ther

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“…Synthesis of 11 C-Nicotine Radiochemistry 11 C-nicotine was produced via N-methylation of (S)-nornicotine using 11 C-methyltriflate prepared by a previously reported method with minor modifications (21). Briefly, 11 C-methyltriflate (FXc-Pro module; GE Healthcare) was bubbled through a solution of 0.25 mg of (S)-nor-nicotine biscamsylate and 10 mL of a 5% solution of 1,2,2,6,6-pentamethyl piperidine in acetonitrile.…”

Section: Subjectsmentioning

confidence: 99%

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

et al. 2016

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This study assessed the in vivo distribution of 11 C-nicotine and the absorbed radiation dose from whole-body 11 C-nicotine PET imaging of 11 healthy (5 male and 6 female) subjects. Methods: After an initial CT attenuation scan, 11 C-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 11 C-nicotine in the liver, red marrow, brain, and lungs were 0.048 6 0.010, 0.031 6 0.005, 0.021 6 0.004, and 0.020 6 0.005 h, respectively. The mean effective dose for 11 C-nicotine was 5.44 6 0.67 mSv/MBq. The organs receiving the highest absorbed dose from the 11 C-nicotine injection were the urinary bladder wall (14.68 6 8.70 mSv/MBq), kidneys (9.56 6 2.46 mSv/ MBq), liver (8.94 6 1.67 mSv/MBq), and spleen (9.49 6 3.89 mSv/ MBq). The renal and hepatobiliary systems were the major clearance and excretion routes for radioactivity. Conclusion: The estimated radiation dose from 11 C-nicotine administration is relatively modest and would allow for multiple PET examinations on the same subject.Key Words: 11 C nicotine; radiation absorbed dose; PET dosimetry; whole-body PET imaging J Nucl Med 2017; 58: 473-478 DOI: 10.2967/jnumed.116.180059 The rate of smoking by adults has decreased substantially in the United States since the hallmark 1964 U.S. Surgeon General's report. Nonetheless, 40 million Americans still smoke regularly, and approximately 400,000 people die each year from illnesses directly associated with smoking (1). Although the various components of tobacco cause different effects, nicotine has been identified as one of the primary chemicals responsible for tobacco addiction in humans (2,3). More recently, there has been a steady rise in the use of newly developed nicotine delivery devices (such as e-cigarettes) to replace cigarettes, and their use has now surpassed that of any other tobacco product, especially among highschool students (4). There is growing concern among the scientific, medical, and regulatory communities over the deleterious impact of nicotine consumption on human health. Aside from the reinforcing action, nicotine perpetuates the smoking habit in humans through the aversive consequences of nicotine withdrawal, a negative reinforcement phenomenon (5-7). Neuronal nicotinic acetylcholine receptors have been identified as one of the primary sites of action in the brain for the elicitation of reinforcing effects, dependency, and withdrawal expressions during cessation of smoking (8)(9)(10)(11)(12). PET imaging is highly useful for studying the impact of smoking ...

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“…C-nicotine was synthesized following an established protocol (Halldin et al, 1992). Approximately 740 MBq 11 C-nicotine, dissolved in 10 ml ethanol, was applied to the tip of the tobacco rod of the study cigarette.…”

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confidence: 99%

Sex-Specific Effects of Cigarette Mentholation on Brain Nicotine Accumulation and Smoking Behavior

Zuo

Mukhin

Garg

et al. 2014

Neuropsychopharmacol

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Menthol cigarettes are likely associated with greater risks of smoking dependence than non-menthol cigarettes. We sought to test the hypothesis that menthol increases the rate of brain nicotine accumulation (BNA) during smoking and thereby enhances its addictive effects. In a counter-balanced cross-over design, 10 menthol and 9 non-menthol smokers (10 females and 9 males; mean age 44.3) underwent two study phases. In each phase, the participant smoked exclusively either menthol or non-menthol research cigarettes for approximately 1 week prior to a positron emission tomography (PET) scan session, during which the subject's head was scanned following inhalation of a single puff of smoke from a cigarette containing 11 C-nicotine. No differences in initial slope, C max , area under curve (AUC), and T 1/2 of BNA were found between menthol and non-menthol cigarettes across all subjects; however, menthol relative to non-menthol cigarettes were associated with steeper initial slopes in men (p ¼ 0.008). Unexpectedly, women had faster BNA as indicated by greater values of the initial slope, C max , AUC, and shorter T 1/2 than men (all pso0.04). The rates of BNA were significantly correlated with ratings of smoking motivations of getting a 'rush', getting relaxing effects and marginally with alleviation of craving. These results do not provide strong support for the putative role of menthol in enhancing BNA, although further studies should explore the apparent effect of menthol on BNA in men. Fast BNA during smoking and preference of sensory properties of menthol cigarettes may independently or jointly contribute to smoking dependence among women.

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(S)- and (R)-[11C]nicotine and the metabolite ()-[11C]cotinine. preparation, metabolite studies and in vivo distribution in the human brain using PET

Cited by 52 publications

References 21 publications

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

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

Sex-Specific Effects of Cigarette Mentholation on Brain Nicotine Accumulation and Smoking Behavior

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(S)- and (R)-[11C]nicotine and the metabolite ()-[11C]cotinine. preparation, metabolite studies and in vivo distribution in the human brain using PET

Cited by 52 publications

References 21 publications

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

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

Sex-Specific Effects of Cigarette Mentholation on Brain Nicotine Accumulation and Smoking Behavior

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