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

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

Bioorganic & medicinal chemistry (2014-07-16)
Natasha Arksey, Tayebeh Hadizad, Basma Ismail, Maryam Hachem, Ana C Valdivia, Rob S Beanlands, Robert A deKemp, Jean N DaSilva
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Diethyl ether, SAJ first grade, ≥99.0%
Sigma-Aldrich
Diethyl ether, JIS special grade, ≥99.5%
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Diethyl ether, JIS 1000, ≥99.5%, for residue analysis
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Acetonitrile solution, contains 10.0% acetone, 0.05% formic acid, 40.0% 2-propanol
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Diethyl ether, for residue analysis, JIS 5000
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Diethyl ether, JIS 300, ≥99.5%, for residue analysis
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Diethyl ether, ≥99.5%
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Acetonitrile solution, contains 0.05 % (w/v) ammonium formate, 5 % (v/v) water, 0.1 % (v/v) formic acid, suitable for HPLC
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Diethyl ether, contains 1 ppm BHT as inhibitor, anhydrous, ≥99.7%
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Acetonitrile solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC
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Acetonitrile solution, contains 0.05 % (v/v) trifluoroacetic acid
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Acetonitrile solution, contains 0.1 % (v/v) formic acid, suitable for HPLC
Supelco
Residual Solvent - Acetonitrile, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Losartan potassium, United States Pharmacopeia (USP) Reference Standard
Supelco
Diethyl ether, analytical standard
Losartan potassium, European Pharmacopoeia (EP) Reference Standard
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Diethyl ether, suitable for HPLC, ≥99.9%, inhibitor-free
Supelco
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Diethyl ether, reagent grade, ≥98%, contains ≤2% ethanol and ≤10ppm BHT as inhibitor
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Diethyl ether, ACS reagent, ≥98.0%, contains ≤2% ethanol and ≤10ppm BHT as inhibitor
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Diethyl ether, contains BHT as inhibitor, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
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Diethyl ether, puriss., contains ~5 mg/L 2,6-di-tert.-butyl-4-methylphenol as stabilizer, meets analytical specification of Ph. Eur., BP, ≥99.5% (GC)
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Diethyl ether, ACS reagent, anhydrous, ≥99.0%, contains BHT as inhibitor
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Diethyl ether, anhydrous, ACS reagent, ≥99.0%, contains BHT as inhibitor
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Acetonitrile, for chromatography
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Acetonitrile, ≥99.8%, suitable for HPLC
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Acetonitrile, SAJ first grade, ≥99.0%
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Pentane, SAJ special grade, ≥99.0%
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Trifluoroacetic acid, SAJ special grade, ≥99.0%
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