Phosphonate-Ligand Simplifies Scandium Theranostic Chemistry - ChemistryViews

Scandium isotopes are emerging as powerful tools for cancer theranostics, a strategy that combines disease imaging and treatment using closely matched radioactive elements. However, the reactive metal must be trapped in a molecular ‘cage’, and many of the best available molecular carriers for imaging and therapy require high temperatures for their synthesis.

Sandrine Huclier-Markai, Nantes Université, France, and colleagues have developed a new ‘ligand’, a phosphonate-based compound called Lp (2,6-bis[(N,N-bis(methylene phosphonic acid)aminomethyl] pyridine), which can bind scandium quickly and efficiently under far milder conditions. Forgoing the common use of large, cage-like “macrocyclic” molecules in radiopharmaceutical chemistry, the team engineered a smaller non-macrocyclic molecule with phosphonate ‘claws’ for metal binding.

The researchers showed that Lp forms a stable one-to-one complex with scandium and can label the medically important isotopes scandium-44 (⁴⁴Sc) and scandium-47 (⁴⁷Sc) with yields above 98% at room temperature in just a few minutes. This performance is particularly notable because commonly used chelators such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) often require heating for efficient labelling.

By using techniques such as ¹H NMR, ³¹P NMR, ⁴⁵Sc NMR, and radiotracer extraction experiments, the researchers were able to demonstrate how they “captured” scandium inside the compound using the available oxygen atoms from the phosphonate moieties. The molecule was stable in human serum and resistant to enzymatic hydrolysis and hydroxyapatite precipitation, a property commonly used to mimic the in vivo behavior of metal-based radiopharmaceuticals.

When the team tested the Lp-scandium complex ([⁴⁷Sc]Sc-Lp) in mice, it was rapidly cleared from circulation through the kidneys, a useful finding in terms of clinical translation.

While Lp does not surpass the strongest existing scandium chelators in thermodynamic stability, it offers something different: rapid, efficient radiolabelling under gentle conditions. The researchers believe this combination could make it easier to build next-generation scandium-based imaging and therapeutic agents, bringing more flexible and accessible theranostic radiopharmaceuticals closer to the clinic.

- Nonmacrocyclic Phosphonic-Based Ligand for Theranostics Applications With 44/47Sc: From Complexation to Biodistribution

Sandrine Huclier-Markai, Théo Demartinecourt, Shelbie J. Cingoranelli, Elsa Jourdain, Cyrille Alliot, Volkan Tekin, Loïc J. Charbonnière, Suzanne E. Lapi

Eur. J. Inorg. Chem. 2026

https://doi.org/10.1002/ejic.70333