PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with ¹⁸F-AZAN, a Radioligand with Optimal Brain Kinetics

Abstract

We evaluated (2)-2-(6-[ 18 F]fluoro-2,39-bipyridin-59-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ( 18 F-AZAN), a novel radiotracer that binds to a4b2 nicotinic acetylcholine receptors (a4b2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and test-retest reliability (n 5 5) and proposed initial quantification of 18 F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the a4b2-nAChRselective partial agonist varenicline. Results: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for 18 F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BP ND ) using plasma reference graphical analysis, which showed excellent reproducibility of BP ND (test-retest variability , 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP ND values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n 5 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of 18 F-AZAN brain uptake in smokers and varenicline-treated subjects. Conclusion: 18 F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity a4b2-nAChR in the living human brain.

Human biodistribution and dosimetry of [ 18 F]nifene, an α4β2* nicotinic acetylcholine receptor PET tracer

“…Human dosimetry studies have been performed for several 18 F-labeled α4β2* nAChR PET tracers [16–18] and are compared to [ 18 F]nifene in Figure 3. Overall, individual organ doses and whole body effective doses are similar between the various radiotracers with the greatest differences present in the urinary bladder wall.…”

Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (−)-[18F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain

“…First, the kinetic properties of 2-[ 18 F]FA-85380 and 5-[ 123 I]IA-85380 are slow and require lengthy imaging protocols of at least 5 h, presenting major logistical barriers to frequent imaging sessions. This has prompted the development of second-generation ${\alpha }_4{\beta }_2^{\ast }$-nAChR specific radioligands, including [ 18 F]nifene (Hillmer et al, 2012), [ 18 F]AZAN (Wong et al, 2013), and (−)-[ 18 F]flubatine (Sabri et al, 2015), with faster kinetic properties and shorter scanning protocols. A second limitation is that conventional PET outcome measures of distribution volumes or binding potentials have restricted interpretation to ligand-receptor binding properties at equilibrium.…”

Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes

“…The identified brain regions overlapped either with neural circuits involved in visuospatial attention and/or are characterized by high densities of nicotinic ACh receptors and responsiveness to nicotinic stimulation in human pharmacological MRI studies. Nicotinic receptors in the primate brain are primarily of the α4β2 subtype, are located on presynaptic boutons and are highly abundant in the thalamus and striatum [49, 50]. …”