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

Bioorg Med Chem. 2009 Dec 1;17(23):7971-7. doi: 10.1016/j.bmc.2009.10.016. Epub 2009 Oct 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / chemical synthesis*
  • Angiotensin II Type 1 Receptor Blockers / chemistry
  • Angiotensin II Type 1 Receptor Blockers / pharmacokinetics
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Binding, Competitive
  • Carbon Radioisotopes / chemistry
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Methylation
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / analysis
  • Spectrophotometry, Infrared
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacokinetics
  • Tetrazoles / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Carbon Radioisotopes
  • Radiopharmaceuticals
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • methyl-2-ethoxy-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylate
  • candesartan