Promising Performance of 4HMS, a New Zirconium-89 Octadendate Chelator

Abstract

Over the last decade, the interest in zirconium-89 (⁸⁹Zr) as a positron-emitting radionuclide increased considerably because of its standardized production and its physical half-life (78.41 h), which matches the biological half-life of antibodies and its successful use in preclinical and clinical applications. So far, desferrioxamine (DFO), a commercially available chelator, has been mainly used as a bifunctional chelating system. However, there are some concerns regarding the <i>in vivo</i> stability of the [⁸⁹Zr]Zr-DFO complex. In this study, we report the synthesis of an acyclic <i>N</i>-hydroxy-<i>N</i>-methyl succinamide-based chelator (4HMS) with 8 coordination sites and our first investigations into the use of this new chelator for ⁸⁹Zr complexation. <i>In vitro</i> and <i>in vivo</i> comparative studies with [⁸⁹Zr]Zr-4HMS and [⁸⁹Zr]Zr-DFO are presented. The 4HMS chelator was synthesized in four steps starting with an excellent overall yield. Both chelators were quantitatively labeled with ⁸⁹Zr within 5-10 min at pH 7 and room temperature; the molar activity of [⁸⁹Zr]Zr-4HMS exceeded (>3 times) that of [⁸⁹Zr]Zr-DFO. [⁸⁹Zr]Zr-4HMS remained stable against transmetalation and transchelation and cleared from most tissues within 24 h. The kidney, liver, bone, and spleen uptakes were significantly low for this ⁸⁹Zr-complex. Positron emission tomography images were in accordance with the results of the biodistribution in healthy mice. Based on DFT calculations, a rationale is provided for the high stability of ⁸⁹Zr-4HMS. This makes 4HMS a promising chelator for future development of ⁸⁹Zr-radiopharmaceuticals.