Evaluation of [¹⁸F]AZAN for quantification of nicotinic acetylcholine receptors in human brain

Objectives Although being expected to broaden our understanding of neuropsychiatric disorders and drug development, quantification of nAChR is confounded by the 'slow' kinetics of previously available PET ligands. We evaluated [¹⁸F]AZAN for quantification of nAChR in the human brain particularly to examine whether the 'faster' kinetics resolve this technical limitation.

Methods Ten healthy subjects (5 males; age 27-61 years) without neuropsychiatric disorders were studied with PET following a bolus injection of [¹⁸F]AZAN (5-15 mCi; mass: 0.08-1.56 μg) for 90 min. Distribution volume (V_T) of MRI-defined volumes of interest (VOIs) were obtained by one- and two-tissue compartment model (OTM and TTC), plasma reference graphical analysis (PRGA; Logan et al., 1990).

Results Time activity curves (TACs) of regions including thalamus peaked around 10 min in all cases and declined monotonously thereafter. Akaike information criteria supported OTM over TTM, which suggested that association/dissociation processes may not be dissociated. PRGA yielded essentially identical V_T estimates as OTM (PRGA = 1×OTM + 0.59; R² = 0.958). Regional V_T was highest at 20.1 ± 6.9 (SD) ml/ml in thalamus, followed by putamen (9.9 ± 1.2 ml/ml), and cortical regions (>8.0 ml/ml). Strong suppression of [¹⁸F]AZAN binding with nicotine was confirmed in one subject who happened to consume nicotine gums chronically. The prediction formula of the bolus-plus-infusion scheme (Carson et al., 1993) indicated 60 min to steady-state in thalamus, a substantial improvement over the 480 min established for [¹⁸F]2FA (Kimes et al., 2008).

Conclusions [¹⁸F]AZAN showed kinetics in the human brain that was fast enough to estimate V_T in 90 min PET scans, suggesting a significant improvement over excising PET ligand (e.g., [¹⁸F]2FA). The study showed that OTM or PRGA may be applicable for V_T estimation of the radioligand. Further studies are underway to estimate the reproducibility of the radioligand.

Research Support NIDA, NIHM, Philips Morris Research (DFW