title: Synthesis and evaluation of the novel 2-[¹⁸F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT₁ receptors.
abstract: The 2-[(18)F]fluoro-3-pent-4-yn-1-yloxypyridine ([(18)F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [(18)F]FPyKYNE to azide-modified tetrazole-protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30 min. Upon co-administration with AT₁R blocker candesartan (2.5, 5 and 10 mg/kg), a dose-dependent reduction (47-65%) in tracer uptake was observed in the kidney, while no difference was observed following AT₂R blocker PD123,319 (5 mg/kg), indicating binding selectivity for AT₁R over AT₂R and potential for imaging AT₁R using PET.
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Arksey
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada.
authors.forename: Tayebeh
authors.initials: T
authors.lastname: Hadizad
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Basma
authors.initials: B
authors.lastname: Ismail
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Hachem
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Valdivia
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: deKemp
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montreal, University of Montreal Hospital Research Centre (CRCHUM), Montréal, Québec, Canada. Electronic address: jean.dasilva@umontreal.ca.
authors.forename: Jean N
authors.initials: JN
authors.lastname: DaSilva
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005462:Fluorine Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C045574:1H-tetrazole; D019808:Losartan; C023666:pyridine; C081643:candesartan
keywords: AT(1); Click chemistry; FPyKYNE; Fluorine-18; Losartan; PET