RESUMEN
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.
Asunto(s)
Quelantes/farmacología , Desoxicitidina/análogos & derivados , Radioisótopos de Galio/química , Compuestos Heterocíclicos/farmacología , Radiofármacos/farmacología , Animales , Quelantes/síntesis química , Desoxicitidina/síntesis química , Desoxicitidina/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos con 1 Anillo , Ratones Endogámicos BALB C , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , GemcitabinaRESUMEN
Gemcitabine analogues with a lipophilic 4-N-alkyl chain bearing a terminal ß-keto sulfonate moiety suitable for fluorination compatible with 18F-radiolabeling have been explored. Displacement of p-toluenesulfonylamino in protected 4-N-tosylgemcitabine with 1-amino-10-undecene gave 4-N-(10-undecenyl)-3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluorocytidine. Oxidation of the terminal double bond in the latter with OsO4/NMO afforded 4-N-(10,11-dihydroxyundecanyl) derivative. Regioselective sulfonation of primary hydroxyl followed by oxidation of secondary hydroxyl with Collin's reagent yielded desired ß-keto sulfonate analogues 8 or 9. Subsequent displacement of the mesylate or tosylate group with KF in the presence of Kryptofix 2.2.2. or 18-crown-6 ether followed by deprotection with NH3/MeOH gave 4-N-(11-fluoro-10-oxoundecanyl)-2'-deoxy-2',2'-difluorocytidine 11.
