title: 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.
authors.affiliation: National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada ON K1Y 4W7.
authors.forename: Tayebeh
authors.initials: T
authors.lastname: Hadizad
authors.forename: Sheryn A
authors.initials: SA
authors.lastname: Kirkpatrick
authors.forename: Samantha
authors.initials: S
authors.lastname: Mason
authors.forename: Kevin
authors.initials: K
authors.lastname: Burns
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Jean N
authors.initials: JN
authors.lastname: Dasilva
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008745:Methylation; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis; D013055:Spectrophotometry, Infrared; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C582420:methyl-2-ethoxy-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylate; C081643:candesartan