Evaluation and metabolite studies of 125I- and 123I-labelled E-(R,R)-IQNP:: Potential radioligands for visualization of M1 muscarinic acetylcholine receptors in brain

A new ligand for the M-1 muscarinic receptor subtype, E-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-IQNP), was labelled with I-125 and I-123 for autoradiographic studies on human whole-brain cryosections and SPET studies, respectively, in Cynomolgus monkey. Autoradiography demonstrated E-[I-125]IQNP binding in M-1 receptor-rich regions such as the neocortex and the striatum. The binding was displaceable by the selective M-1 antagonist biperiden. In vivo single photon emission tomography (SPET) studies with E-[I-123]IQNP demonstrated a high accumulation of radioactivity in the monkey neocortex, Rapid hydrolysis of the quinuclidinyl ester to the free acid was found to be a major biotransformation route for E-[I-123]IQNP. The free acid of E-[I-123]IQNP does not pass the blood-brain barrier, but the plasma concentration was high as compared to the total radioactivity in brain. It is thus necessary to correct for the high concentration of radioactive metabolites in parenchymal blood (CBV) to obtain accurate values for E-[I-123]IQNP binding in brain. (C) 1998 Elsevier Science Inc.