Gemcitabine (2', 2'-difluoro-2'-deoxycytidine, dFdC) is used to treat tumors caused by several types of cancer. For some time, our lab has explored developing 4-N-acyl and 4-N-alkyl gemcitabine analogues which can be radiolabeled for use in PET imaging. Recent advances in aza-crown ethers bifunctional chelators with the ability to bind gallium generated significant interest in 68Ga-based radiopharmaceuticals/radiotracers. Gallium itself possesses anti-proliferative properties in various cancers which is mainly attributed to its ability to mimic Fe3+. Among bifunctional chelator, NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) complexation site has a coordination cavity highly accommodating to Ga(III). This encouraged us to investigate 4-N-alkyl gemcitabine analogues conjugated with 2-(p-isothiocyanatobenzyl)-NOTA (SCN-Bn-NOTA) for 68Ga-labelling. The conjugation of 4-N-(3-aminopropanyl) gemcitabine with SCN-Bn-NOTA (0.1 M Na2CO3 buffer at pH 11) at ambient temperature provided 4-N-alkylgemcitabine-NOTA chelator (60%). Incubation of latter with excess of gallium(III) chloride (GaCl3) (0.6 N AcONa/H2O, pH = 9.3) over 15 min gave gallium 4-N-alkylgemcitabine-NOTA complex. 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 (~95%). 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.

4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling

2019 Spring National Meeting

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