Targeted nuclear medicine is an emerging clinical paradigm that harnesses radioactive isotopes for imaging and therapy by capitalizing on differential target expression of diseased and healthy cells. Development of clinically applicable radiopharmaceuticals requires carefully matching the physical half-life of the radioisotope with the biological half-life of the targeting vector to ensure optimal target accumulation within a relevant timeframe. Radioisotopes of scandium exhibit decay properties ideally suited for targeted imaging and therapy with small biologics, such as antibody fragments. Namely, ⁴³Sc (Eβ⁺_avg = 476 keV, t_1/2= 3.9 h) and ⁴⁴Sc (Eβ⁺_avg = 632 keV, t_1/2= 4 h) enable prolonged positron emission tomography (PET) imaging up to 24 hours post injection, while the emission properties of ⁴⁷Sc (Eβ⁻_avg = 162 keV, t_1/2= 80.4 h) are well-suited for subsequent therapeutic intervention. However, strategies to chelate scandium isotopes under conditions compatible with thermally sensitive biologics to afford inert complexes is critically lacking.

Currently, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is considered the gold standard Sc³⁺chelator, but the slow complexation kinetics require radiolabeling at 80 C for at least 30 minutes. To address this, we rationally designed a triaza-macrocycle derived chelator, L2, that is well-matched to the ionic radii and coordination preferences of Sc³⁺, as supported by density functional theory (DFT) calculations and pH-dependent UV speciation. Radiolabeling studies with ⁴⁴Sc at room temperature indicate that L2 affords a 250-fold increase in apparent molar activity relative to our first-generation chelator, mpatcn (L1), and a 3-fold increase relative to DOTA at 80 C. Proof-of-concept radiolabeling of peptide and antibody conjugates for prostate and breast cancer targeting, respectively, demonstrate compatibility with a wide range of targeting vectors and underscore the potential to expand our scope of imageable and treatable disease targets. Toward this goal, a ⁴⁴Sc-PET imaging and biodistribution study in a pre-clinical model of prostate cancer will be discussed.

Margarita Chernysheva

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