Chelation with a Twist: A Bifunctional Chelator to Enable Room Temperature Radiolabeling and Targeted PET Imaging with Scandium-44

Scandium-44 has emerged as an attractive, novel PET radioisotope with ideal emission properties and half-life (t1/2 = 3.97 h, Emean β+ = 632 keV) well matched to the pharmacokinetics of small molecules, peptides and small biologics. Conjugates of the current gold-standard chelator for 44Sc, 1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid (DOTA), require heating to achieve radiochemical complexation, limiting application of this isotope in conjunction with temperature-sensitive biologics. To establish Sc(III) isotopes as broadly applicable tools for nuclear medicine, development of alternative bifunctional chelators is required. To address this need, we characterized the Sc(III)-chelation properties of the small-cavity triaza-macrocycle-based, picolinate-functionalized chelator H3mpatcn. Spectroscopic and radiochemical studies establish the [Sc(mpatcn)] complex as kinetically inert and appropriate for biological applications. A proof-of-concept bifunctional conjugate targeting the prostate-specific membrane antigen (PSMA), picaga-DUPA, chelates 44Sc to form 44Sc(picaga)-DUPA at room temperature with an apparent molar activity of 60 MBq/μmol and formation of inert RRR-Λ and SSS-Δ-twist isomers. Sc(picaga)-DUPA exhibits a Ki of 1.6 nM for PSMA, comparable to the 18F-based imaging probe DCFPyL (Ki = 1.1 nM) currently in phase 3 clinical trials for imaging prostate cancer. Finally, we successfully employed 44Sc(picaga)-DUPA to image PSMA-expressing tumors in a preclinical mouse model, establishing the picaga bifunctional chelator as an optimal choice for the 44Sc PET nuclide.