Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M₁ and M₂ muscarinic acetylcholine receptors in Alzheimer’s disease

Abstract.

Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (Z-IQNP) has high affinity to the M₁ and M₂ muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[¹²³I]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the non-selective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[¹²³I]IQNP binding in all these regions. The percentage of unchanged Z-[¹²³I]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[¹²³I]IQNP showed higher uptake in M₂-rich regions, compared with previously obtained results with E-[¹²³I]IQNP. In conclusion, the radioactivity distribution from Z-[¹²³I]IQNP in monkey brain indicates that Z-[¹²³I]IQNP binds to the M₁- and M₂-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.