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

The 2-[18F]fluoro-3-pent-4-yn-1-yloxypyridine ([18F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [18F]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.

[18F]FPyKYNE-losartan has been synthesized via click chemistry linking [18F]FPyKYNE to azide-modified tetrazole-protected losartan in multiple steps. Preliminary in vivo small animal imaging with PET in rats displayed high uptake in the kidneys with good contrast to surrounding tissue and specificity binding to renal AT1 receptor.Figure optionsDownload as PowerPoint slide