title: Evaluation of [(11)C]methyl-losartan and [(11)C]methyl-EXP3174 for PET imaging of renal AT1receptor in rats.
abstract: BACKGROUND
  The angiotensin II type 1 receptor (AT1R) is responsible for the main effects of the renin-angiotensin system (RAS), and its expression pattern is altered in several diseases. The [(11)C]methylated derivatives of the clinically used AT1R blocker (ARB) losartan and its active metabolite EXP3174, that binds with higher affinity to AT1R, were evaluated as potential PET imaging tracers in rat kidneys.
  
  
  METHODS
  [(11)C]Methyl-losartan and [(11)C]methyl-EXP3174 were synthesized by [(11)C]methylation of the tetrazole-protected analogs using [11C]methyl iodide. Tissue uptake and binding selectivity of [(11)C]methyl-losartan were assessed by ex-vivo biodistribution and in-vitro autoradiography. Radiolabeled metabolites in rat plasma and kidneys were analysed by column-switch HPLC. Both tracers were evaluated with small animal PET imaging. Due to better pharmacokinetics, [(11)C]methyl-EXP3174 was further investigated via PET by co-injection with AT1R antagonist candesartan or the AT2R antagonist PD123,319.
  
  
  RESULTS
  Binding selectivity to renal AT1 over AT2 and Mas receptors was demonstrated for [(11)C]methyl-losartan. Plasma metabolite analysis at 10 min revealed stability of [(11)C]methyl-losartan and [(11)C]methyl-EXP3174 with the presence of unchanged tracer at 70.8 ± 9.9% and 81.4 ± 6.0%, of total radioactivity, respectively. Contrary to [(11)C]methyl-losartan, co-injection of candesartan with [(11)C]methyl-EXP3174 reduced the proportion of unchanged tracer (but not metabolites), indicating that these metabolites do not bind to AT1R in rat kidneys. MicroPET images for both radiotracers displayed high kidney-to-background contrast. Candesartan significantly reduced [(11)C]methyl-EXP3174 uptake in the kidney, whereas no difference was observed following PD123,319 indicating binding selectivity for AT1R.
  
  
  CONCLUSIONS
  [(11)C]Methyl-EXP3174 displayed a favorable binding profile compared to [(11)C]methyl-losartan for imaging renal AT1Rs supporting further studies to assess its full potential as a quantitative probe for AT1R via PET.
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada, K1H 8M5.
authors: Basma
authors: B
authors: Ismail
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7.
authors: Tayebeh
authors: T
authors: Hadizad
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7.
authors: Rawad
authors: R
authors: Antoun
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7.
authors: Mireille
authors: M
authors: Lortie
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7.
authors: Robert A
authors: RA
authors: deKemp
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada, K1H 8M5.
authors: Rob S B
authors: RS
authors: Beanlands
authors: National Cardiac PET Centre, Division of Cardiology (Department of Medicine) University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada, K1Y 4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada, K1H 8M5; Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montreal, University of Montreal Hospital Research Centre (CRCHUM), Montréal, Québec, Canada H2X 0A9. Electronic address: jean.dasilva@umontreal.ca.
authors: Jean N
authors: JN
authors: DaSilva
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019808:Losartan / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C066026:losartan carboxylic acid; D019808:Losartan
keywords: Active metabolite of losartan; Carbon-11 radiolabelling; Kidney imaging