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Specific Beta-Adrenergic Receptor Binding of Carazolol Measured with PET

Departments of Radiology and Chemistry, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio

Correspondence: For correspondence or reprints contact: Marc S. Berridge, PhD, Division of Nuclear Radiology, University Hospitals of Cleveland, 2074 Abington Rd., Cleveland, OH 44106.

ABSTRACT

Carazolol is a promising high-affinity beta-adrenergic receptor ligand for the noninvasive determination of beta receptor status using PET. Earlier investigations demonstrated specific receptor binding of carazolol in mice. These PET studies with S(-)-[2''-¹¹C]carazolol in pigs were performed to explore the utility of the tracer for PET receptor studies. Methods: Tracer uptake in the heart and lung was measured by PET as a function of time. Receptors were blocked with propranolol and different doses of ICI 118,551 to estimate specific binding. Fluorine-18-1''-Fluoro-carazolol and the less active R-enantiomer of [¹¹C]-carazolol were also studied. Results: Specific receptor binding was 75% of the total uptake in the heart, preventable and displaceable by propranolol. Dose-dependent competition showed that carazolol binds in vivo to ß₁ and to ß₂ subtypes. Uptake of the labeled R(+) enantiomer of carazolol was not receptor-specific. Conclusions: Carazolol labeled with ¹¹C or ¹⁸F is a strong candidate for use in receptor estimation with PET. The in vivo observations were consistent with its known high affinity and slow receptor dissociation rate. Its high specific receptor uptake and low metabolism allow existing kinetic models to be applied for receptor measurements. The ¹¹C label is convenient for repeated administrations, though ¹⁸F allowed the long observation periods necessary for measurement of the receptor dissociation rate. If needed, nonspecific uptake can be estimated without pharmacologic intervention by using the labeled R enantiomer.

Key Words: PET • beta-adrenoceptors • heart • carazolol

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