Synthesis and evaluation of the novel 2-[¹⁸F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT₁ receptors

Natasha Arksey; Tayebeh Hadizad; Basma Ismail; Maryam Hachem; Ana C Valdivia; Rob S Beanlands; Robert A deKemp; Jean N DaSilva

doi:10.1016/j.bmc.2014.06.011

Synthesis and evaluation of the novel 2-[¹⁸F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT₁ receptors

Bioorg Med Chem. 2014 Aug 1;22(15):3931-7. doi: 10.1016/j.bmc.2014.06.011. Epub 2014 Jun 17.

Authors

Natasha Arksey¹, Tayebeh Hadizad², Basma Ismail¹, Maryam Hachem¹, Ana C Valdivia¹, Rob S Beanlands¹, Robert A deKemp², Jean N DaSilva³

Affiliations

¹ 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.
² Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada.
³ 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: [email protected].

PMID: 25023539
DOI: 10.1016/j.bmc.2014.06.011

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.

Keywords: AT(1); Click chemistry; FPyKYNE; Fluorine-18; Losartan; PET.

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 / pharmacology
Animals
Benzimidazoles / pharmacology
Biphenyl Compounds
Fluorine Radioisotopes / chemistry
Kidney / diagnostic imaging
Kidney / drug effects
Kidney / metabolism
Losartan / chemical synthesis
Losartan / chemistry*
Losartan / pharmacology
Male
Positron-Emission Tomography
Pyridines / chemistry
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 / chemistry*
Receptor, Angiotensin, Type 1 / metabolism
Tetrazoles / chemistry
Tetrazoles / pharmacology

Substances

Angiotensin II Type 1 Receptor Blockers
Benzimidazoles
Biphenyl Compounds
Fluorine Radioisotopes
Pyridines
Radiopharmaceuticals
Receptor, Angiotensin, Type 1
Tetrazoles
1H-tetrazole
Losartan
pyridine
candesartan