RESUMO
The conjugation of 4-N-(3-aminopropanyl)-2'-deoxy-2',2'-difluorocytidine with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1â¯M Na2CO3 buffer (pH 11) at ambient temperature provided 4-N-alkylgemcitabine-NOTA chelator. Incubation of latter with excess of gallium(III) chloride (GaCl3) (0.6â¯N AcONa/H2O, pHâ¯=â¯9.3) over 15â¯min gave gallium 4-N-alkylgemcitabine-NOTA complex which was characterized by HRMS. Analogous [68Ga]-complexation of 4-N-alkylgemcitabine-NOTA conjugate proceeded with high labeling efficiency (94%-96%) with the radioligand almost exclusively found in the aqueous layer (â¼95%). The high polarity of the gallium 4-N-alkylgemctiabine-NOTA complex resulted in rapid renal clearance of the 68Ga-labelled radioligand in BALB/c mice.
Assuntos
Quelantes/farmacologia , Desoxicitidina/análogos & derivados , Radioisótopos de Gálio/química , Compostos Heterocíclicos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Animais , Quelantes/síntese química , Desoxicitidina/síntese química , Desoxicitidina/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos com 1 Anel , Camundongos Endogâmicos BALB C , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , GencitabinaRESUMO
The coupling of gemcitabine with functionalized carboxylic acids (C9-C13) or reactions of 4-N-tosylgemcitabine with the corresponding alkyl amines afforded 4-N-alkanoyl and 4-N-alkyl gemcitabine derivatives. The analogues with a terminal hydroxyl group on the alkyl chain were efficiently fluorinated under conditions that are compatible with protocols for (18)F labeling. The 4-N-alkanoylgemcitabines showed potent cytostatic activities in the low nanomolar range against a panel of tumor cell lines, whereas cytotoxicity of the 4-N-alkylgemcitabines were in the low micromolar range. The cytotoxicity for the 4-N-alkanoylgemcitabine analogues was reduced approximately by 2 orders of magnitude in the 2'-deoxycytidine kinase (dCK)-deficient CEM/dCK(-) cell line, whereas cytotoxicity of the 4-N-alkylgemcitabines was only 2-5 times lower. None of the compounds acted as efficient substrates for cytosolic dCK; therefore, the 4-N-alkanoyl analogues need to be converted first to gemcitabine to display a significant cytostatic potential, whereas 4-N-alkyl derivatives attain modest activity without measurable conversion to gemcitabine.