Are [O-methyl-11C]derivatives of ICI 89,406 β1- adrenoceptor selective radioligands suitable for PET?

Abstract

Purpose: Radioligand binding studies show that β1- adrenoceptor (β1-AR) density may be reduced in heart disease without down regulation of β2-ARs. Radioligands are available for measuring total β-AR density non-invasively with clinical positron emission tomography (PET) but none are selective for β1- or β2-ARs. The aim was to evaluate ICI 89,406, a β1-AR-selective antagonist amenable to labelling with positron emitters, for PET. Methods: The S-enantiomer of an [O-methyl-11C] derivative of ICI 89,406 ((S)-[11C]ICI-OMe) was synthesised. Tissue radioactivity after i.v. injection of (S)-[11C]ICI-OMe (< 2 nmol•kg-1) into adult Wistar rats was assessed by small animal PET and post mortem dissection. Metabolism was assessed by HPLC of extracts prepared from plasma and tissues and by measuring [11C]CO2 in exhaled air. Results: The heart was visualised by PET after injection of (S)-[11C]ICI-OMe but neither unlabelled (S)-ICI-OMe nor propranolol (non-selective β-AR antagonist) injected 15 min after (S)-[ 11C]ICI-OMe affected myocardial radioactivity. Ex vivo dissection showed that injecting unlabelled (S)-ICI-OMe, propranolol or CGP 20712A (β1-selective AR antagonist) at high dose (> 2 μmol·kg-1) before (S)-[11C]ICI-OMe had a small effect on myocardial radioactivity. HPLC demonstrated that radioactivity in myocardium was due to unmetabolised (S)-[11C]ICI-OMe although 11C-labelled metabolites rapidly appeared in plasma and liver and [11C]CO2 was detected in exhaled air. Conclusion: Myocardial uptake of (S)-[11C]ICI-OMe after i.v. injection was low, possibly due to rapid metabolism in other tissues. Injection of unlabelled ligand or β-AR antagonists had little effect indicating that binding was mainly to non-specific myocardial sites, thus precluding the use of (S)-[ 11C]ICI-OMe to assess β1-ARs with PET. © 2007 Springer-Verlag.