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European Journal of Nuclear Medicine and Molecular Imaging

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01.01.2008 | Original Article

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

verfasst von: Marilyn P. Law, Stefan Wagner, Klaus Kopka, Victor W. Pike, Otmar Schober, Michael Schäfers

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 1/2008

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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.

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Titel: Are [O-methyl-11C]derivatives of ICI 89,406 β1-adrenoceptor selective radioligands suitable for PET?
verfasst von: Marilyn P. Law
Stefan Wagner
Klaus Kopka
Victor W. Pike
Otmar Schober
Michael Schäfers
Publikationsdatum: 01.01.2008
Verlag: Springer-Verlag
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 1/2008
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-007-0553-8

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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