Development of acyclic chelates for incorporation into theranostic radiopharmaceuticals for cancer

Radioactive metals possess various chemical and physical properties (e.g., half-life, radioactive decay), making them aptly suited for the diagnosis and treatment (theranostics) of cancer. Securing the radiometal in a drug complex for safe delivery into the tumor site is crucial for the successful clinical application of these radioactive drugs called radiopharmaceuticals. A fundamental component of a radiopharmaceutical is the chelate, a ligand that tightly binds the radiometal forming a stable radioactive complex, which is then covalently attached to a disease targeting molecule such as a peptide or an antibody through a linker. In the past two decades, intense research efforts have expanded the production of radiometals suitable for radiopharmaceutical applications such as titanium-45 (45Ti) and actinium-225 (225Ac), among many others. To this end, some of these radiometals have shown excellent preclinical and clinical results. However, the stable chelation in vivo of these radiometals remains a challenge resulting in the need to develop novel chelates tailored to the properties of each radioisotope. This work focuses on developing novel acyclic chelates for the stable chelation of the cutting-edge first-row transition metals scandium-44/47 (44/47Sc) and 45Ti, the radiolanthanides lanthanum-135 (135La) and terbium-155/161 (155/161Tb), and the radioactinides 225Ac and thorium-227 (227Th). For this purpose, we exploited the oxophylic 1,2-hydroxypyridinone (1,2-HOPO) moiety through a pentaamine backbone on a decadentate chelate (HOPO-O10) for the larger radiometals and on a tripodal backbone for a hexadentate chelate (HOPO-O6-C4) along with its catechol amide version (CAM-O6-C4) for the smaller radiometals. These three chelates were synthesized, their coordination chemistry was characterized using the corresponding non-radioactive complexes, and they were evaluated in radiolabeling studies to determine their potential for incorporation into radiopharmaceuticals. HOPO-O10 was found to be an excellent candidate for 161Tb and 227Th with high in vitro stability. A simpler version of HOPO-O10, HOPO-O8, was used for incorporation into a radiopharmaceutical for which a novel tetrazine-containing bifunctional chelate analogue (HOPO-O8-Me-Tz) was prepared and evaluated in a preclinical animal study with encouraging results for zirconium-89 (89Zr), a possible imaging pair for 227Th. Moreover, HOPO-O6-C4 showed excellent affinity for 47Sc and promising complex stability in vivo.