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

PMID25023539

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

Y0001062

Losartan potassium, European Pharmacopoeia (EP) Reference Standard

296082

Sigma-Aldrich

Diethyl ether, contains 1 ppm BHT as inhibitor, anhydrous, ≥99.7%

574732

Sigma-Aldrich

Acetonitrile solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC

574724

Sigma-Aldrich

Acetonitrile solution, contains 0.05 % (v/v) trifluoroacetic acid

576956

Sigma-Aldrich

Acetonitrile solution, contains 0.1 % (v/v) formic acid, suitable for HPLC

179272

Sigma-Aldrich

Diethyl ether

91238

Supelco

Diethyl ether, analytical standard

685461

Sigma-Aldrich

Acetonitrile solution, contains 10.0% acetone, 0.05% formic acid, 40.0% 2-propanol

309966

Sigma-Aldrich

Diethyl ether, suitable for HPLC, ≥99.9%, inhibitor-free

V800156

Supelco

Diethyl ether, suitable for HPLC, contains 5 ppm BHT as stabilizer, ≥99%

V800155

Sigma-Aldrich

Diethyl ether, LR, contains 5 ppm BHT as stabilizer, ≥99.5%

V800157

Sigma-Aldrich

Diethyl ether, anhydrous, contains 5 ppm BHT as stabilizer, ≥99.5%

V800154

Sigma-Aldrich

Diethyl ether, AR, contains 5 ppm BHT as stabilizer, ≥99.5%

676845

Sigma-Aldrich

Diethyl ether, ACS reagent, ≥98.0%, contains ≤2% ethanol and ≤10ppm BHT as inhibitor

1370462

USP

Losartan potassium, United States Pharmacopeia (USP) Reference Standard

PHR1320

Supelco

Residual Solvent - Acetonitrile, Pharmaceutical Secondary Standard; Certified Reference Material

673811

Sigma-Aldrich

Diethyl ether, anhydrous, ACS reagent, ≥99.0%, contains BHT as inhibitor

32203

Sigma-Aldrich

Diethyl ether, contains BHT as inhibitor, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)

346136

Sigma-Aldrich

Diethyl ether, ACS reagent, anhydrous, ≥99.0%, contains BHT as inhibitor

24004

Sigma-Aldrich

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)

346144

Sigma-Aldrich

Diethyl ether, reagent grade, ≥98%, contains ≤2% ethanol and ≤10ppm BHT as inhibitor

675415

Sigma-Aldrich

Acetonitrile, HPLC Plus, ≥99.9%, poly-coated bottles

74564

Supelco

Trifluoroacetic acid, analytical standard

74875

Sigma-Aldrich

8-Octanoyloxypyrene-1,3,6-trisulfonic acid trisodium salt, suitable for fluorescence, ≥90% (HPCE)