Bioorganic & Medicinal Chemistry 2014-08-01

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

文献索引：Bioorg. Med. Chem. 22(15) , 3931-7, (2014)

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摘要

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.Copyright © 2014 Elsevier Ltd. All rights reserved.