SPET imaging of central muscarinic acetylcholine receptors with iodine-123labelled E-IQNP and Z-IQNP

1-Azabicyclo[2.2.2]oct-3-yl alpha -hydroxy-alpha-(1-iodo-1-propen-3-yl)-alp ha -phenylacetate (IQNP) is a muscarinic acetylcholine receptor (mAChR) ant agonist and the racemic ligand contains eight stereoisomers. In a single-ph oton emission tomography (SPET) study in monkeys we recently confirmed that [I-123]E-(R,R)-IQNP ([I-123]E-IQNP) is a radioligand with modest selectivi ty for the M-1 and M-4 subtypes, whereas [I-123]Z(R,R)-IQNP ([I-123]Z-IQNP) is non-subtype selective. In the present SPET study, E- and Z-IQNP were ex amined in human subjects. SPET examination was performed on three male subj ects after i.v. injection of [I-123]E-IQNP and in another three after i.v. injection of [I-123]Z-IQNP. The binding potential (BP) for [I-123]E-IQNP wa s calculated using several quantitative approaches with the cerebellum as a reference region, High-performance liquid chromatography was used to measu re radioligand metabolism in plasma. Following [I-123]E-IQNP, the radioacti vity was hi,oh in the neocortex and striatum, intermediate in the thalamus and low in the pens and cerebellum, which is consistent with the rank order for the regional. density of M-1 and M-4 subtypes in vitro, For all region s, peak equilibrium was identified within the 48-h data acquisition. The si mplified reference tissue approach using SPET data from 0 to 48 h was the m ost reliable in this limited series of subjects. Following injection of [I- 123]Z-IQNP, radioactivity was high in the neocortex and striatum, intermedi ate in the thalamus and pens and low in the cerebellum, which is in agreeme nt with the density of M-1, M-2 and M-4 subtypes as measured in vitro. Quan titative analyses provided indirect support for specific M-2 binding of Z-I QNP in the cerebellum, The high selectivity of [I-123]E-IQNP for M-1 and M- 4 receptors allowed the use of cerebellum as a reference region devoid of s pecific binding, and may be advantageous for applied clinical studies of M- 1 and M-4 receptors binding in man. [I-123]Z-IQNP has potential for explora tion of M-2 receptor binding in the cerebellum.