Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET.

INTRODUCTION: Angiotensin II type 1 (AT(1)) receptors play a key role in the regulation of renal and cardiovascular functions and have been implicated in the pathogenesis of many diseases. The aim of this study was to assess binding of the novel radioligand [(11)C]methyl-candesartan to AT(1) receptors in the rat kidney in vivo with PET. METHODS: Dynamic PET images were acquired for 60 min at baseline, with coinjection of candesartan (5 mg/kg), and after injection of PD123,319 (5 mg/kg). Volumes of distribution (R(C)∙V(T)) were estimated with a two-compartment model, by Logan analysis, and by taking the tissue-to-plasma activity ratio at 50-60 min post-injection. RESULTS: The two-compartment model did not describe the kinetics at baseline adequately and the baseline scans were too short to obtain accurate estimates of R(C)∙V(T) with the Logan approach. Based on the tissue-to-plasma ratios, roughly one-third of V(T) at baseline could be attributed to AT(1) receptor binding. There were no indications of AT(2) receptor binding in the rat kidney. CONCLUSION: It may be possible to detect changes in AT(1) receptor density in the rat kidney in vivo with [(11)C]methyl-candesartan and PET. Imaging AT(1) receptors with PET may provide valuable information on the role of these receptors in the pathogenesis of diseases such as hypertension, diabetic nephropathy, ventricular remodeling, and heart failure.

Novel O-[(11)C]methylated derivatives of candesartan as angiotensin II AT(1) receptor imaging ligands: radiosynthesis and ex vivo evaluation in rats.

[(11)C]Methyl-candesartan and its desethyl derivative ([(11)C]TH4) were developed as potential radiotracers for imaging angiotensin II (Ang II) type 1 (AT(1)) receptors. These compounds were synthesized via methylation of tetrazole-protected candesartan using [(11)C]methyl iodide followed by deprotection through HCl hydrolysis at 65 degrees C to produce [(11)C]methyl-candesartan, and 90 degrees C for [(11)C]TH4. Ex vivo biodistribution and competition studies were carried out for both [(11)C]methyl-candesartan and [(11)C]TH4 to assess tissue retention time course and binding selectivity. Besides the liver, [(11)C]methyl-candesartan and [(11)C]TH4 displayed highest tissue retention in the AT(1) receptor-rich renal cortex and outer medulla. At tracer doses 15 min post-injection, [(11)C]methyl-candesartan demonstrated higher specific binding proportion for AT(1) receptors, and selectivity for AT(1) over Ang II AT(2), Mas, beta-adrenergic, and alpha(2)-adrenergic receptors in rat kidneys compared to [(11)C]TH4. This study indicates that [(11)C]methyl-candesartan has potential for in vivo imaging renal AT(1) receptors selectively using positron emission tomography.