Synthesis and Preclinical Evaluation of Bifunctional Ligands for Improved Chelation Chemistry of ⁹⁰Y and ¹⁷⁷Lu for Targeted Radioimmunotherapy

Abstract

We report a practical and high yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, C-NOTA, and 3p-C-DEPA for radiolabeling kinetics with 90Y and 177Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with 90Y and 177Lu. 90Y-3p-C-NETA-trastuzumab and 177Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of 177Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. 177Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using 90Y and 177Lu and has potential to replace DOTA and DTPA analogues in current clinical use.

Novel hexadentate and pentadentate chelators for 64Cu-based targeted PET imaging

“…In our continued effort on improved chelation chemistry for development of radiopharmaceuticals, 10–14 we synthesized and evaluated new hexadentate and pentadentate NOTA analogues (Figure 1) as potential chelators of 64 Cu. The new chelators were evaluated for radiolabeling with 64 Cu to determine the maximum specific activity and radiolabeling kinetics with 64 Cu under mild condition.…”

A comparative evaluation of the chelators H 4 octapa and CHX-A″-DTPA with the therapeutic radiometal 90 Y

“…A newer and more suitable chelator for this radiometal pair is CHX-A″-DTPA, which – in contrast to DOTA – can be effectively radiolabeled at ambient temperatures within 15–30 min [26–31]. Although DOTA and CHX-A″-DTPA are the most established Y 3+ chelators, a new NOTA derivative 3p-C-NETA has also been used with 177 Lu, 86 Y, and 90 Y and gives high radiolabeling yields in only 5 min at room temperature [32–34]. …”

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu

“…10–12 Octadentate DOTA, with a larger macrocyclic platform, forms stable complexes with Y(III) and Lu(III), although slow complexation kinetics of DOTA with the lanthanides remains a major drawback for its practical RIT applications. 13,14 In general, acyclic chelators such as DTPA analogues rapidly bind to a metal. However, acyclic DTPA are known to form less stable complexes than macrocyclic DOTA.…”

“…12,14–18 The design of the bimodal chelates is based on hypothesis that the chelators sequester a metal with enhanced complexation kinetics and a high level of complex stability via cooperative and bimodal coordination of macrocyclic and acyclic binding moieties. We proposed that the acyclic pendant donor groups in the chelates can rapidly capture and initiate coordination of the metal, as in the case of the acyclic chelate DTPA, and the macrocyclic component tightly wraps up the cation trapped in the acyclic donor groups achieving maximum complex stability, as in the case of a macrocyclic chelate NOTA or DOTA.…”

“…12 The octadentate NETA conjugated to trastuzumab, a tumor-targeting antibody, was found to instantly complex 90 Y and 177 Lu, and the corresponding 90 Y or 177 Lu-radiolabeled complexes were stable in human serum and tumor-bearing mice. 14 …”