The recent US Food and Drug Administration (FDA) approval of numerous ⁶⁸Ga/ ¹⁷⁷Lu-based radiopharmaceuticals underscores the potential of radiometals in diagnostic and therapeutic nuclear medicine. However, ⁶⁸Ga³⁺ and ¹⁷⁷Lu³⁺complexes possess disparate coordination chemistry and in vivo behavior, leading to discrepancies where the diagnostic tracer does not accurately predict the distribution and behavior of the radiotherapeutic. This shortcoming can be addressed if both radioisotopes are of the same chemical element (e.g., ^86/90Y, ^44/47Sc) or exhibit chemical homology (⁴⁴Sc/ ⁹⁰Y/ ¹⁷⁷Lu) and therefore possess matched coordination chemistry and in vivo behavior. Such matched pairs represent a powerful tool to non-invasively identify target expression, stratify patients for subsequent therapeutic intervention, and monitor therapeutic response.
The ⁴⁴Sc/ ⁴⁷Sc/ ⁹⁰Y/ ¹⁷⁷Lu isotope tetrad of small rare earth radiometals share similarities in ionic radii and coordination preference yet chemical approaches to utilize these isotopes under mild conditions compatible with a wide range of targeting vectors is critically lacking. To address this gap, we rationally designed a triaza-macrocycle derived chelator, H₄mphospatcn, that is well-matched to the ionic radii and coordination preferences of Sc(III), Y(III) and Lu(III), as supported by computational studies and pH-dependent speciation. Preliminary studies indicate that H₄mphospatcn enables low-temperature (< 40°C) radiolabeling and retains complex inertness with ⁴⁴Sc, ⁸⁶Y, and ¹⁷⁷Lu. Here, we explore four different strategies to produce a bifunctional derivative that maintains the favorable radiolabeling properties and kinetic inertness of H₄mphospatcn to enable ⁴⁴Sc-imaging and ⁴⁷Sc/ ⁹⁰Y/ ¹⁷⁷Lu-therapy applications.

Shin Hye Ahn

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