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

Bioorg Med Chem. 2018 Nov 15;26(21):5624-5630. doi: 10.1016/j.bmc.2018.10.007. Epub 2018 Oct 12.

Abstract

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 0.1 M Na2CO3 buffer (pH 11) at ambient temperature provided 4-N-alkylgemcitabine-NOTA chelator. Incubation of latter with excess of gallium(III) chloride (GaCl3) (0.6 N AcONa/H2O, pH = 9.3) over 15 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 (∼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.

Keywords: 68-Gallium; Gemcitabine; NOTA; Nucleosides; PET imaging; Prodrugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents / chemical synthesis
  • Chelating Agents / pharmacology*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemical synthesis
  • Deoxycytidine / pharmacology
  • Gallium Radioisotopes / chemistry*
  • Gemcitabine
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology*
  • Heterocyclic Compounds, 1-Ring
  • Mice, Inbred BALB C
  • Positron-Emission Tomography / methods
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacology*

Substances

  • Chelating Agents
  • Gallium Radioisotopes
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 1-Ring
  • Radiopharmaceuticals
  • Deoxycytidine
  • 1,4,7-triazacyclononane-N,N',N''-triacetic acid
  • Gallium-68
  • Gemcitabine