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摘要
The bifunctional chelator NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) shows remarkably high Ga(III) complexation efficiency and comprises one carboxylic acid moiety which is not involved into metal ion coordination. An improved synthetic protocol affords NOPO with 45% overall yield. Stepwise protonation constants (log Ka), determined by potentiometry, are 11.96, 5.22, 3.77, and 1.54; the stability constant of the Ga(III) complex is log K-GaL = 25.0. Within 5 min, Ga-68(III) incorporation by NOPO is virtually quantitative at room temperature between pH 3 and 4, and at 95 degrees C at pH ranging from 0.5 to 7, at NOPO concentrations of 30 mu M and 10 mu M, respectively. During amide bond formation at the distant carboxylate using the HATU coupling reagent, an intramolecular phosphinic acid ester (phosphilactone) is formed, which is cleaved during Ga-68 complexation or in acidic media, such as trifluoroacetic acid (TFA). Phosphilactone formation can also be suppressed by complexation of Zn2+ prior to conjugation, the resulting zinc-containing conjugates nevertheless being suitable for direct Ga-68-labeling. In AR42J (rat pancreatic carcinoma) xenografted CD-1 nude mice, Ga-68-labeled NOPO-NaI(3)-octreotide conjugate (Ga-68-NOPO-NOC) showed high and fully blockable tumor uptake (13.9 +/- 5% ID/g, 120 min p.i., compared to 0.9 +/- 0.4% ID/g with 5 mg/kg of nonlabeled peptide). Uptake in other tissues was generally below 3% ID/g, except appearance of excretion-related activity accumulation in kidneys. NOPO-functionalized compounds tend to be more hydrophilic than the corresponding DOTA- and NODAGA-conjugates, thus promoting fast and extensive renal excretion of Ga-68-NOPO-radiopharmaceuticals. NOPO-functionalized peptides provide suitable pharmacokinetics in vivo and meet all requirements for efficient Ga-68-labeling even at room temperature in a kit-like manner.
- 出版日期2014-11
