title: Are [O-methyl-11C]derivatives of ICI 89,406 beta1-adrenoceptor selective radioligands suitable for PET?
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Str. 33, 48149, Münster, Germany. mplaw@uni-muenster.de
authors: Marilyn P
authors: MP
authors: Law
authors: Stefan
authors: S
authors: Wagner
authors: Klaus
authors: K
authors: Kopka
authors: Victor W
authors: VW
authors: Pike
authors: Otmar
authors: O
authors: Schober
authors: Michael
authors: M
authors: Schäfers
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000388:Air / Q000032:analysis; D000818:Animals; D002245:Carbon Dioxide / Q000032:analysis / Q000097:blood / Q000737:chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry; D045853:Exhalation; D008024:Ligands; D008297:Male; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D011412:Propanolamines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011433:Propranolol / Q000008:administration & dosage / Q000378:metabolism; D011851:Radioactivity; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D000319:Adrenergic beta-Antagonists; D002250:Carbon Radioisotopes; D008024:Ligands; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D002245:Carbon Dioxide; D011433:Propranolol; C025716:ICI 89406