Metal-based radiopharmaceuticals have become integral to mainstream cancer treatment, as evidenced by the recent clinical translation of numerous ⁶⁸Ga- and ¹⁷⁷Lu-based agents for sequential imaging and therapy.^1,2 The success of such established isotopes has catalyzed advancements in the production and purification of radionuclides with varied half-lives and emission properties.³ Among these emerging nuclides, radioisotopes of scandium exhibit decay properties ideally suited for targeted imaging (⁴⁴Sc: Eβ⁺_avg = 632 keV, t_1/2= 4 h) and therapy (⁴⁷Sc: Eβ^–_avg = 162 keV, t_1/2 = 80.4 h) with targeting vectors ranging in size from small molecules to antibody fragments.⁴ Diagnostic imaging with ⁴⁴Sc offers improved prognosis of the distribution and dosing of ¹⁷⁷Lu therapy relative to the ⁶⁸Ga analog, highlighting the potential to expand our theranostic toolbox.⁵ However, there is a critical lack of strategies to chelate scandium isotopes under conditions compatible with temperature-sensitive targeting vectors, which limits the scope of imageable and treatable diseases.

Currently, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is the gold standard for Sc³⁺ chelation, but slow complexation kinetics necessitate radiolabeling at 80 °C for at least 30 minutes. To address this limitation, we rationally designed a phosphonate-based azamacrocyclic chelator, L2, that is well-matched to the ionic radii and coordination preferences of Sc³⁺ as supported by density functional theory (DFT) calculations and thermodynamic speciation studies. L2 derivatives enable facile radiolabeling with ⁴⁴Sc and ¹⁷⁷Lu at < 40 °C. By modulating the charge and functionalization strategy, we optimized the pharmacokinetic properties of the ⁴⁴Sc and ¹⁷⁷Lu complexes, resulting in identification of a lead peptide-based candidate targeting the prostate-specific membrane antigen (PSMA). Proof-of-concept studies in a pre-clinical model of prostate cancer, including ⁴⁴Sc-PET and ¹⁷⁷Lu-SPECT imaging as well as biodistribution studies, showed promising results: high in vivo stability, excellent tumor uptake, and rapid background clearance (Figure 1). Our results indicate that the L2 ligand family is a versatile platform for low-temperature chelation with ⁴⁴Sc and ¹⁷⁷Lu, providing compatibility with small molecule and biological targeting vectors of interest. 

Image/Figure:

Click to view full size

Image/Figure Caption:

Low-temperature (< 40 °C) radiolabeling of novel PSMA-targeted phosphonate-based azamacrocyclic chelator affords in vivo compatible 44Sc-PET (left) and 177Lu-SPECT (right) imaging agent in a pre-clinical murine model of prostate cancer. Both nuclear imaging modalities demonstrate excellent PSMA+ tumor conspicuity. 

Author