Investigating the Theranostic Potential of Elementally Matched [⁴³Sc]Sc-PSMA-617 and [⁴⁷Sc]Sc-PSMA-617

The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate ⁴³Sc, the diagnostic nuclide, and ⁴⁷Sc, the therapeutic nuclide, as a theranostic pair.

Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [⁴³Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1-9 h. LNCaP tumor-bearing mice injected with [⁴⁷Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [⁴³Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [⁴⁷Sc]Sc-PSMA-617.

⁴³Sc and ⁴⁷Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [⁴⁷Sc]Sc-PSMA-617. In vivo PET studies showed specificity of [⁴³Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [⁴⁷Sc]Sc-PSMA-617 up to 48 h. [⁴⁷Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [⁴³Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [⁴⁷Sc]Sc-PSMA-617, showing that ⁴³Sc PET data can predict therapeutic outcomes in individual animals from ⁴⁷Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line.

Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated in vivo stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher ⁴³Sc PET SUV_mean was strongly correlated to therapeutic response from the ⁴⁷Sc agent, demonstrating that ⁴³Sc and ⁴⁷Sc can be used as an elementally matched theranostic pair.