Application of carbon-11 labelled nicotine in the measurement of human cerebral blood flow and other physiological parameters

Abstract

Using positron emission tomography (PET), we measured the regional cerebral blood flow (rCBF) in five normal human subjects after intravenous injection of carbon-11 labeled (R)nicotine. The rCBF of the same subjects was measured by PET using the C15O2 inhalation steady-state method. The distribution of 11C activity in the brain after injection of 11C-(R)nicotine was almost equivalent to the CBF image obtained with the C15O2 inhalation stead-state method. The kinetics of 11C-(R)nicotine in the brain was analysed using a two-compartment model consisting of vascular and brain tissue compartments. The rCBF values obtained with 11C-(R)nicotine were higher than with C15O2 gas. The relatively long fixed distribution of 11C-(R)nicotine with a short uptake period allows stimulation studies by measurement of CBF to be performed with better photon flux and a longer imaging time than are possible with H215O.

Pharmacokinetics of radiotracers in human plasma during positron emission tomography

“…A single nonpolar metabolite, earlier identified as [ 11 C]norcotenine (Yokoi et al, 1993), eluted at 7.5 min (Fig. 1D).…”

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

“…Positron emission tomography (PET) imaging with drugs labeled with carbon-11 is a powerful method for measuring the pharmacokinetics of drugs directly in the human brain (Piel et al, 2014;Volkow et al, 1999;Fowler et al, 1999). Nicotine has been radiolabeled with carbon-11 and its distribution has been measured in healthy subjects and in patients with neurological and psychiatric disorders after intravenous administration (Mazière et al, 1976;Långström et al, 1982;Halldin et al, 1992;Yoko et al, 1993;Muzic et al, 1998). [ 11 C]Nicotine availability has also provided the opportunity to measure its distribution and kinetics in the brain and other organs after different routes of administration.…”

“…In this study we required a method for reliably synthesizing [ 11 C]nicotine in the freebase form and formulating it in a small volume of ethanol which could be spiked into a cigarette or other nicotine delivery device. We evaluated the literature methods for radiolabeling nicotine with carbon-11 including the first radiosynthesis by reductive alkylation of nornicotine with [ 11 C]formaldehyde (Mazière et al, 1976) and several other methods via alkylation with [ 11 C]methyl iodide (Långström et al, 1982;Halldin et al, 1992;Yoko et al, 1993;Apana et al, 2010). Most of these methods used the salt form of nornicotine with the addition of an organic base such as tetramethylpiperidine (TMP) to liberate the freebase with heating at elevated temperatures (85-140 o C).…”

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

“…PET is considered superior to SPECT due to the higher sensitivity of the instrumentations and better quantification of regional tissue concentrations of radioisotope-labeled molecular entities. There are numerous published studies related to receptor binding (Sihver et al 1998) and brain uptake and distribution of nicotine in animals, (Maziere et al 1976; Saji et al 1992; Sihver et al 1999; Nordberg et al 1989), healthy subjects (Bergstrom et al 1995; Lunell et al 1996; Zuo et al 2017; Apana and Berridge 2010; Berridge et al 2010; Rose et al 2010; Halldin et al 1992; Yokoi et al 1993; Nyback et al 1994; Muzic et al 1994; Garg et al 2017), and patients with neurological disorders (Nordberg et al 1990; Kadir et al 2006; Kadir et al 2007) after inhalation using a vapor inhaler (Bergstrom et al 1995; Lunell et al 1996), or a device (Zuo et al 2017), or a [ 11 C]nicotine spiked cigarette (Lunell et al 1996; Apana and Berridge 2010; Berridge et al 2010; Rose et al 2010) and intravenous administration (Halldin et al 1992; Yokoi et al 1993; Nyback et al 1994; Muzic et al 1994; Garg et al 2017; Nordberg et al 1990; Kadir et al 2006; Kadir et al 2007) of [ 11 C]-labeled nicotine. For nicotine brain uptake and distribution in humans, the positron emission tomography technique was used.…”