Click Chemistry Enables [Zr]Zr-DOTA Radioimmunoconjugation for Theranostic Zr-immunoPET.

There have been predictions that the use of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in zirconium-89 (Zr) immuno-positron emission tomography (Zr-immunoPET) could enhance the in vivo stability of Zr radioimmunoconjugates. However, conjugating [Zr]Zr-DOTA to a monoclonal antibody (mAb) remains a challenge as the heat treatment required for [Zr]Zr-DOTA chelation can lead to thermal denaturation of the mAb moieties. We developed a method for synthesizing [Zr]Zr-DOTA-mAb based on a tetrazine (Tz)-conjugated bifunctional DOTA derivative 2,2',2″-(10-(1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)-3,21,26-trioxo-6,9,12,15,18-pentaoxa-29-carboxy-2,22,25-triazanonacosane-29-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-Tz) and the inverse electron-demand Diels-Alder (IEDDA) click chemistry reaction where -cyclooctene-modified mAbs are conjugated to [Zr]Zr-DOTAGA without being exposed to heat.

Radiolabeling of PSMA-617 with Zr: A novel use of DMSO to improve radiochemical yield and preliminary small-animal PET results.

Introduction: Novel diagnostic and therapeutic options are urgently needed for patients with metastatic castration-resistant prostate cancer (CRPC). PSMA-617 is one of the most promising ligands that bind to prostate specific membrane antigen (PSMA), the cell surface biomarker of CRPC. Of the radiolabeled PSMA ligands developed to date, [Ga]Ga-PSMA-617 is most commonly used for PSMA positron emission tomography (PET) prior to radioligand therapy (RLT) with [Lu]Lu-PSMA-617.