Polyazamacrocycle Ligands Facilitate ⁸⁹Zr Radiochemistry and Yield ⁸⁹Zr Complexes with Remarkable Stability

Abstract

Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 ( 89 Zr: t 1/2 = 78.4 h, β + : 22.8%, E β+max = 901 keV; EC: 77%, E γ = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the 89 Zr 4+ ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2′,2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9, pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2′,2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [ 89 Zr]Zr-PCTA and [ 89 Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.

The Race for Hydroxamate-Based Zirconium-89 Chelators

“…In a recent paper the same group evaluated smaller macrocyclic chelators, such as NOTA, TRITA and PCTA (Figure 2d) in an effort to overcome the hurdle of elevated temperature. Indeed, NOTA and PCTA could be radiolabeled under mild conditions (37 • C) and the radiolabeled chelators (no bioconjugation data available) showed good in vitro and in vivo characteristics [21].…”

State of the Art in Radiolabeling of Antibodies with Common and Uncommon Radiometals for Preclinical and Clinical Immuno-PET

“…However, to the best of our knowledge, 89 Zr-DOTA-mAb conjugates have not been evaluated in vivo yet. 55,56 Of note, development of novel candidate chelators for 89 Zr remains a very active field as exemplified by the recent introduction of oxoDFO*, 57,58 FSC derivatives, 59 4HMS, 60 DFO2, 61 PCTA, 62 and NOTA. 62 However, for most of these chelators the suitability for stable, efficient, and inert 89 Zr labeling of mAbs still has to be demonstrated, while in vivo evaluation to prove their superiority over DFO and DFO* is lacking.…”

“…Because of the high temperature (90 °C) needed for radiolabeling DOTA with 89 Zr, a prelabeling approach is required comprising the conversion of 89 Zr-oxalate to 89 Zr-chloride followed by radiolabeling of DOTA and then coupling to an antibody. However, to the best of our knowledge, 89 Zr-DOTA-mAb conjugates have not been evaluated in vivo yet. , Of note, development of novel candidate chelators for 89 Zr remains a very active field as exemplified by the recent introduction of oxoDFO*, , FSC derivatives, 4HMS, DFO2, PCTA, and NOTA . However, for most of these chelators the suitability for stable, efficient, and inert 89 Zr labeling of mAbs still has to be demonstrated, while in vivo evaluation to prove their superiority over DFO and DFO* is lacking.…”

The impact of zirconium‐89 solution formulation on the efficiency of [89Zr]Zr‐deferoxamine synthesis

“…This approach allows high yield recovery of 89 Zr to be achieved in a small volume of eluate. Nonetheless, the proposed methods are used only in a small number of studies because of the high propensity for hydrolysis of [ 89 Zr]Zr‐chloride 32,34–38 . Another drawback, which is controversial, is negative affect of chloride ions on the stability of radioimmunoconjugates.…”

“…Nonetheless, the proposed methods are used only in a small number of studies because of the high propensity for hydrolysis of [ 89 Zr]Zr-chloride. 32,[34][35][36][37][38] Another drawback, which is controversial, is negative affect of chloride ions on the stability of radioimmunoconjugates. Autoradiolysis leads to the formation of OCl À radicals, which react with the SH-group of the enolated thiourea unit.…”