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

Abstract

The radioligand 2-[ 18 F]F-A-85380 has been used for PET studies of the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) in the living brain of humans and nonhuman primates. In order to extend the capacity of microPET to quantify neuroreceptors in rat brain, we carried out studies of 2-[ 18 F]F-A-85380 to measure the apparent bindng potential BP* in individual rats, which were studied repeatedly over several months. Using a bolus-plus-infusion paradigm, 2-[ 18 F]F-A-85380 (specific activity 20 -1300 GBq/μmol) was administered intravenously over 8 to 9 h with K bol values of 350 to 440 min and a mean infusion rate of 0.03 ± 0.01 nmol/kg/h. Studies included a 2-h nicotine infusion initiated 2 h before the end of scanning to displace specifically bound radioactivity. Steady state binding in brain was obtained within 5 h as defined by the occurrence of constant radioactivity concentrations in brain regions and constant, free arterial plasma levels of nonmetabolized radioligand. BP* averages (± SEM) for thalamus, forebrain, and cerebellum were 5.9 ± 0.7, 2.6 ± 0.4, and 1.0 ± 0.1, respectively, which are consistent with the α4β2* nAChR distribution in rat brain measured in vitro. Studies of receptor occupancy determined the ED 50 to be 0.29 nmol/kg/h. The demonstration that α4β2* nAChRs are quantifiable in the rat brain using PET measurements, coupled with the ability to conduct longitudinal studies over several months in the same rats, suggests potential applications to studies of chronic nicotine use, its treatment, and abnormal functioning of α4β2* receptors in a rat model.

The effects of lobeline on α4β2* nicotinic acetylcholine receptor binding and uptake of [18F]nifene in rats

“…The displacement of [ 18 F]nifene in the cerebellum observed with the experiments reported herein indicate the presence of significant α4β2* nAChR binding in the rat cerebellum. This finding is in agreement with studies using an analog radioligand of [ 18 F]nifene, 2-[ 18 F]FA-85380, which found the cerebellum to contain small amounts of specific binding in the rat brain (Vaupel et al, 2007). Since no MRI data was acquired for partial volume correction or precise region delineation, the identified ROI may have contained spill-in signal from surrounding structures or slightly inaccurate region identification.…”

Evaluation of [18F]Nifene biodistribution and dosimetry based on whole-body PET imaging of mice

“…The currently established agonist PET radiotracer for α4β2 receptors in use in humans is 2-[ 18 F]FA-85380 [12]. The main drawback of this radioligand is the long PET acquisition time usually required to achieve transient equilibrium (>5 hours) [13]. [ 18 F]Nifene is being developed as a PET agent with faster kinetics as a potential superior alternative to 2-[ 18 F]FA-85380 for the non-invasive study of nAChRs in the brain.…”

Impact of short access nicotine self-administration on expression of α4β2* nicotinic acetylcholine receptors in non-human primates

“…Different PET radiotracers have been developed for α4β2* nAChRs quantification (Horti et al 2013). Among those PET radiotracers, 2-[ 18 F]fluoro-A-85380 (2-FA) has been used in rodents (Vaupel et al 2007), non-human primates (Chefer et al 2003; Le Foll et al 2007a; Le Foll et al 2009; Valette et al 2003; 2005) and human subjects (Mukhin et al 2008), with an upregulation of nAChRs reported in human smokers (Brody et al 2013; Mukhin et al 2008; Wullner et al 2008). Similar nAChR upregulation in the brains of smokers has been observed using a Single Photon Emission Computed Tomography and analog of 2FA, 5-[ 123 I]iodo-A-85380 (Staley et al 2006).…”