Preclinical evaluation of an 18F-labelled beta1-adrenoceptor selective radioligand based on ICI 89,406.
OBJECTIVE
Radioligand binding studies indicate a down-regulation of myocardial beta(1)-adrenoceptors (beta(1)-AR) in cardiac disease which may or may not be associated with a decrease in beta(2)-ARs. We have chosen ICI 89,406, a beta(1)-selective AR antagonist, as the lead structure to develop new beta(1)-AR radioligands for PET and have synthesised a fluoro-ethoxy derivative (F-ICI).


METHODS
(S)-N-[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N'-[4-(2-[(18)F]fluoro-ethoxy)-phenyl]-urea ((S)-[(18)F]F-ICI) was synthesised. Myocardial uptake of radioactivity after intravenous injection of (S)-[(18)F]F-ICI into adult CD(1) mice or Wistar rats was assessed with positron emission tomography (PET) and postmortem dissection. Metabolism was assessed by high-performance liquid chromatography analysis of plasma and urine.


RESULTS
The heart was visualised with PET after injection of (S)-[(18)F]F-ICI but neither unlabelled F-ICI nor propranolol (non-selective beta-AR antagonist) injected 15 min after (S)-[(18)F]F-ICI affected myocardial radioactivity. Ex vivo dissection demonstrated that predosing with propranolol or CGP 20712 (beta(1)-selective AR-antagonist) did not affect myocardial radioactivity. Radiometabolites rapidly appeared in plasma and both (S)-[(18)F]F-ICI and radiometabolites accumulated in urine.


CONCLUSIONS
Myocardial uptake of (S)-[(18)F]F-ICI after intravenous injection was mainly at sites unrelated to beta(1)-ARs. (S)-[(18)F]F-ICI is not a suitable beta(1)-selective-AR radioligand for PET.
Law
Marilyn P
MP
Department of Nuclear Medicine, University Hospital Münster, D-48149 Münster, Germany. mplaw@uni-muenster.de
Wagner
Stefan
S
Kopka
Klaus
K
Renner
Christiane
C
Pike
Victor W
VW
Schober
Otmar
O
Schäfers
Michael
M
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D008024:Ligands; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011854:Radiochemistry; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D013379:Substrate Specificity
D005462:Fluorine Radioisotopes; D008024:Ligands; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; C025716:ICI 89406
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