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

Abstract

1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP) is a muscarinic acetylcholine receptor (mAChR) antagonist and the racemic ligand contains eight stereoisomers. In a single-photon emission tomography (SPET) study in monkeys we recently confirmed that [123I]E-(R,R)-IQNP ([123I]E-IQNP) is a radioligand with modest selectivity for the M1 and M4 subtypes, whereas [123I]Z-(R,R)-IQNP ([123I]Z-IQNP) is non-subtype selective. In the present SPET study, E- and Z-IQNP were examined in human subjects. SPET examination was performed on three male subjects after i.v. injection of [123I]E-IQNP and in another three after i.v. injection of [123I]Z-IQNP. The binding potential (BP) for [123I]E-IQNP was calculated using several quantitative approaches with the cerebellum as a reference region. High-performance liquid chromatography was used to measure radioligand metabolism in plasma. Following [123I]E-IQNP, the radioactivity was high in the neocortex and striatum, intermediate in the thalamus and low in the pons and cerebellum, which is consistent with the rank order for the regional density of M1 and M4 subtypes in vitro. For all regions, peak equilibrium was identified within the 48-h data acquisition. The simplified reference tissue approach using SPET data from 0 to 48 h was the most reliable in this limited series of subjects. Following injection of [123I]Z-IQNP, radioactivity was high in the neocortex and striatum, intermediate in the thalamus and pons and low in the cerebellum, which is in agreement with the density of M1, M2 and M4 subtypes as measured in vitro. Quantitative analyses provided indirect support for specific M2 binding of Z-IQNP in the cerebellum. The high selectivity of [123I]E-IQNP for M1 and M4 receptors allowed the use of cerebellum as a reference region devoid of specific binding, and may be advantageous for applied clinical studies of M1 and M4 receptors binding in man. [123I]Z-IQNP has potential for exploration of M2 receptor binding in the cerebellum.

Towards a muscarinic hypothesis of schizophrenia

“…Some of these shortcomings of IQNB may be overcome with newly developed SPECT-and PET-ligands that bind selectively to specific subtypes of the muscarinic receptor. 103,104 Neuropsychopharmacological studies Muscarinic receptor antagonists (anticholinergics) such as atropine and scopolamine cause cognitive dysfunction in healthy controls 29 and, at higher doses, can induce delirium as well as vivid hallucinations in healthy controls. 105 Despite these potential effects, treatment of subjects with schizophrenia with anticholinergics has been a common practice for many years to alleviate motor side effects caused by first-generation antipsychotics.…”

Human Brain Imaging of Acetylcholine Receptors

“…There has been only one report of human experiments with IQNP (Nobuhara et al, 2001). With regard to PET ligands, [ 11 C]benztropine uptake was observed in the frontal, parietal, occipital, and temporal cortices as well as in subcortical structures, including the corpus striatum and thalamus, in normal human subjects.…”

Nuclear Medicine in Neurodegenerative Disorders

“…But all mAChR ligands demonstrated lack of subtype selectivity and high unspecific cerebral uptake. One of the last introduced ligands is Z‐IQNP (Z‐(R,R)‐1‐azabicyclo(2.2.2)oct‐3‐yl alpha‐hydroxy‐alpha‐(1‐iodo1‐propen‐3‐yl)‐alpha‐phenylacetat), labelled with [123I], which is a muscarinic antagonist with high affinity for the M2 subtype (56).…”