2 [ ¹⁸ F]F‐A85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans

Abstract

Noninvasive imaging of nicotinic acetylcholine receptors (nAChRs) in the human brain in vivo is critical for elucidating the role of these receptors in normal brain function and in the pathogenesis of brain disorders. Here we report the first in vivo visualization of human brain areas containing nAChRs by using PET and 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2-[18F]FA). We acquired scans from six healthy non-smoking volunteers after i.v. bolus administration of 2-[18F]FA (1.6 MBq/kg or 0.043 +/- 0.002 mCi/kg). This dose was sufficient for visualizing nAChRs in the thalamus up to 5 h after injection. There were no adverse effects associated with administration of no-carrier-added 2-[18F]FA (1.3-10 pmol/kg). Consistent with the distribution of nAChRs in human brain, accumulated radioactivity was greatest in thalamus, intermediate in the midbrain, pons, cerebellum, and cortex; and least in white matter. As approximately 90% of the injected radioactivity was eliminated via the urine (biological half-life ca. 4 h), the urinary bladder wall received the highest radiation dose. The estimate of radiation dose equivalent to the urinary bladder wall (ca. 180 +/- 30 mSv/MBq or 0.7 rem/mCi with a 2.4 h void interval) suggests that multiple studies could be performed in a single subject. The results predict that quantitative PET imaging of nAChRs in human brain with 2-[18F]FA is feasible.

Functional brain imaging of tobacco use and dependence

“…Studies of non-human primates and humans have examined distributions of nAChRs with these new tracers, and found regional densities of these receptors similar to those in the animal work cited above (Chefer et al, 1999Fujita et al, 2002;Fujita et al, 2003;Kimes et al, 2003;Valette et al, 1999). In initial human studies, no subjective or cardiovascular effects of 2-FA have been reported; however, studies of tobacco dependent subjects have not yet been published.…”

Quantification of α4β2* nicotinic receptors in the rat brain with microPET® and 2-[18F]F-A-85380

“…2-[ 18 F]F-A-85380 has been successfully used with PET to image α4β2* nAChRs in both humans (Bottlaender et al, 2003;Kimes et al, 2003;Gallezot et al, 2005;Mitkovski et al, 2005;Brody et al, 2006) and nonhuman primates (Chefer et al, 2003a;Valette et al, 2002). Developing imaging strategies to use this radioligand in the rat is of interest because of the widespread use of this species as an animal model to investigate the effects of nicotine.…”

Whole-body radiation dosimetry of 2-[18F]Fluoro-A-85380 in human PET imaging studies

“…Other 11 C-labeled radioligands, such as 3-[(1- [16,17], however, spatial resolution and sensitivity of SPECT are generally lower than those of PET. 2-[ 18 F]FA lacks some of the disadvantages of previous nAChR probes [1,18], and exhibits high accumulation in the human thalamus [1], consistent with the known brain regional distribution of nAChRs [19]. Parallel work has been done using another compound of this series, 6-[ 18 F]FA [20].…”

“…studies of nicotinic acetylcholine receptors (nAChRs) in the human brain [1]. Such studies have the potential to elucidate the role of nAChRs in normal brain function as well as in pathological states that are thought to involve these receptors (e.g., Alzheimer's disease,…”