Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease

Rationale: The density of the M2 subtype of muscarinic acetylcholine recept ors (mAChR) has been shown to be reduced in the brain of patients with Alzh eimer's disease (AD). It is therefore of interest to develop a brain imagin g method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2] oct-3-yl alph a-hydroxy-alpha-(1-iodol-propen-3-yl)-alpha-phenylacetate (Z-IQNP) is a mus carinic antagonist with high affinity for the M2 subtype. Objective. The ph armacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro an d in vivo. Methods: Z-IQNP was labelled with I-125 and I-123. Autoradiograp hy was performed on whole-hemisphere cryosections from human post mortem br ains. SPECT was performed in a cynomolgus monkey. Results: Autoradiography showed binding of [I-125]Z-IQNP in all brain regions, which was inhibited b y the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [I-125]Z-I QNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [I-123]Z-IQNP in all brain r egions. The binding was markedly reduced in all brain regions after pretrea tment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [I-123]Z-IQNP bindin g in the cerebellum, which is consistent with a high density of M2-receptor s in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. Conclusions: This study indi cates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M-2 than the M-1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [I-123]Z-IQNP should be usefu l for future SPECT studies in AD for examination of the density of M2 recep tors particularly in the cerebellum.