The development of theranostic radiolabeled peptides is revolutionizing the standard of care for patients with prostate cancers and neuroendocrine tumors. The current generation of theranostics has a biologically active peptide conjugated to cyclic DOTA-type chelators which delivers either a diagnostic β⁺-emitter (e.g. ⁶⁸Ga) or a therapeutic β^--emitter (e.g. ¹⁷⁷Lu) to a target overexpressed on the cancerous cells. However, since the chemical composition of the two agents in this scenario is not identical, they have different biological properties in vivo. Introducing a second distinct radiolabeling site amenable for ¹⁸F-labeling within a single conjugate promises to address this limitation while also taking advantage of the superior decay properties of fluorine-18 over gallium-68. Here we present the development of a platform for the facile ¹⁸F-labeling of peptides using Heteroaromatic Silicon Fluoride Acceptors (HetSiFA’s) via isotope exchange on silicon. The presence of the chelator for ¹⁷⁷Lu-labeling provides theranostic capabilities to the conjugates. This project has already delivered a series of theranostic candidates targeting the somatostatin receptors SSTR2 that are overexpressed on neuroendocrine tumors, based on either agonists (e.g. TATE) or antagonist (e.g. JR11) peptides. Key features of our HetSiFA-DOTAGA(^natLu)-TATE/JR11 conjugates include excellent isolated radiochemical yields over 50% (max activity yield 24 GBq) and molar activity >160 GBq/µmol in 30 minutes. The most promising candidates showed tunable albumin binding properties in vitro, and renal excretion with low defluorination in vivo, suggesting a favorable pharmacokinetic profile for their potential application as radiopharmaceuticals. Our results illustrate the benefits of HetSiFA technology for the design of theranostic agents.

Simon Edelmann

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