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

ABSTRACT

[(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.