ICI 89406

Clinical, electrocardiographic, and hemodynamic effects of ICI 89,406, a new cardioselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, in patients with angina pectoris.[Pubmed:6156341]

J Cardiovasc Pharmacol. 1980 Jul-Aug;2(4):435-44.

ICI 89,406, a new cardioselective beta-adrenoceptor antagonist possessing marked intrinsic sympathomimetic activity, was administered (0.04 mg/kg, i.v.) to 10 patients with stable, uncomplicated, exercise-induced angina pectoris and angiographically proven coronary artery disease. The drug resulted in a significant reduction in heart rate (from 125 +/- 5 to 110 +/- 4/min, p less than 0.001), mean systemic arterial pressure (from 147 +/- 4 to 137 +/- 3 mm Hg, p less than 0.01), and electrocardiographic ST-segment depression (from 1.9 +/- 0.5 to 0.8 +/- 0.3 mm, p less than 0.01) without any change in pulmonary arterial or wedge pressure during submaximal supine leg exercise on a bicycle ergometer. These changes were accompanied by a reduction of cardiac output in 6/10 patients and of the duration of pain in 8/10 patients. At rest, all the hemodynamic parameters remained essentially unchanged in comparison with the control study. These studies indicate that ICI 89,406 produces effective beta-adrenoceptor blockade during exercise in patients with angina pectoris. The partial agonist activity of the drug may be responsible for the minimal circulatory response at rest.

Are [O-methyl-11C]derivatives of ICI 89,406 beta1-adrenoceptor selective radioligands suitable for PET?[Pubmed:17906860]

Eur J Nucl Med Mol Imaging. 2008 Jan;35(1):174-85.

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