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Measurement of ₄ß₂ Nicotinic Acetylcholine Receptors with [¹²³I]5-I-A-85380 SPECT

Departments of Psychiatry, Diagnostic Radiology, and Pharmacology, Yale University School of Medicine and VA Connecticut, West Haven, Connecticut

Correspondence: For correspondence or reprints contact: Masahiro Fujita, MD, PhD, VA Connecticut/116A2, 950 Campbell Ave., West Haven, CT 06516.

ABSTRACT

Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [¹²³I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels ₄ß₂ nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm. Methods: A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191–226 MBq [¹²³I]5-I-A-85380 and image acquisition for 289–367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74–132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8–5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (–)-cytisine (0.8 and 1.0 mg/kg). Results: The kinetics of this tracer was best described by the 1 -tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V_T') agreed between bolus and B/I paradigms (average percentage difference in V_T' 16.8%). (–)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region. Conclusion: These results show the feasibility of quantifying ₄ß₂ nAChRs using [¹²³I]5-I-A-8538O and support the use of V_T' as an appropriate outcome measure.

Key Words: nicotinic receptors • 3-[2(S)-2-azetidinylmethoxy]pyridine • SPECT • compartment analysis • equilibrium analysis

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