Characterization of the binding properties of carbon-11-labeled candesartan derivatives as potential angiotensin II AT1 receptor radioligands for PET imagiing

Abstract

The renin-angiotensin system (RAS) has been implicated in the pathophysiology of heart failure, hypertension and diabetic nephropathy. Positron emission tomography (PET), a non-invasive imaging modality, can provide information on cellular function and receptor density. Based on previous structure-activity studies, two 11C-labeled analogues of the clinically used AT 1 receptor antagonist candesartan were developed, [11C]-methyl-candesartan and [11C]TH4, and characterized for binding specificity and selectivity. [11C]Methyl-candesartan was further tested to determine the presence of labeled metabolites and potential for small animal PET. [11C]Methyl-candesartan displayed higher specific binding and selectivity to angiotensin II type 1 (AT1) over angiotensin II type 2 (AT2), Mas (Ang(1-7)), beta-adrenergic and alpha 2-adrenergic receptors in kidney regions in ex vivo studies. Selectivity for AT1 over Mas receptors was not observed for [11C]TH4. Renal binding selectivity over AT2 was confirmed in [11C]methyl-candesartan microPET imaging studies. Metabolite analysis of [11 C]methyl-candesartan detected a labeled metabolite in the rat kidney, although the identity has not been determined. The work presented here supports the potential of [11C]methyl-candesartan for in vivo imaging of AT1 receptors.