The Evaluation of (1R,4R,7R,10R)-α,α′,α″,α‴-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTMA) as a Chelator for Zirconium-89

Recently, macrocycles such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) have been observed to form zirconium-89 (⁸⁹Zr: t_½ = 78.4 h, β+: 22.8%, E_β+max = 901 keV; EC: 77%, E_γ = 909 keV)-complexes with excellent in vivo stability. In this report, we describe (<i>1R,4R,7R,10R</i>)-α,α',α″,α‴-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) as an ⁸⁹Zr chelator. Using [⁸⁹Zr]ZrCl₄, [⁸⁹Zr]Zr-DOTMA was prepared in 99% radiochemical yield and a molar activity of 1055 ± 6 MBq/µmol. In vitro studies revealed a LogP value of -2.97± 0.02 and a radiometal complex that was inert when challenged with 1000-fold excess EDTA or high concentrations of biologically relevant metal ions. Finally, biodistribution studies revealed that the radiometal complex demonstrated in vivo behavior that was like [⁸⁹Zr]Zr-DOTA and superior to [⁸⁹Zr]Zr-DFO. Despite these promising observations, the elevated temperature required to form the [⁸⁹Zr]Zr-DOTMA complex and the lack of derivatives available for bioconjugation will require additional ligand engineering to improve its utility for future nuclear medicine applications.