Comparative Study of a Decadentate Acyclic Chelate, HOPO-O, and Its Octadentate Analogue, HOPO-O, for Radiopharmaceutical Applications.

Radiolanthanides and actinides are aptly suited for the diagnosis and treatment of cancer via nuclear medicine because they possess unique chemical and physical properties (e.g., radioactive decay emissions). These rare radiometals have recently shown the potential to selectively deliver a radiation payload to cancer cells. However, their clinical success is highly dependent on finding a suitable ligand for stable chelation and conjugation to a disease-targeting vector. Currently, the commercially available chelates exploited in the radiopharmaceutical design do not fulfill all of the requirements for nuclear medicine applications, and there is a need to further explore their chemistry to rationally design highly specific chelates. Herein, we describe the rational design and chemical development of a novel decadentate acyclic chelate containing five 1,2-hydroxypyridinones, 3,4,3,3-(LI-1,2-HOPO), referred to herein as HOPO-O, based on the well-known octadentate ligand 3,4,3-(LI-1,2-HOPO), referred to herein as HOPO-O, a highly efficient chelator for Zr[Zr]. Analysis by H NMR spectroscopy and mass spectrometry of the La and Tb complexes revealed that HOPO-O forms bimetallic complexes compared to HOPO-O, which only forms monometallic species. The radiolabeling properties of both chelates were screened with [La]La, [Tb]Tb, [Ac]Ac and, [Th]Th. Comparable high specific activity was observed for the [Tb]Tb complexes, outperforming the gold-standard 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, yet HOPO-O surpassed HOPO-O with higher [Th]Th affinity and improved complex stability in a human serum challenge assay. A comprehensive analysis of the decadentate and octadentate chelates was performed with density functional theory for the La, Ac, Eu, Tb, Lu, and Th complexes. The computational simulations demonstrated the enhanced stability of Th-HOPO-O over Th-HOPO-O. This investigation reveals the potential of HOPO-O for the stable chelation of large tetravalent radioactinides for nuclear medicine applications and provides insight for further chelate development.