Chelation with a twist: a bifunctional chelator to enable room temperature radiolabeling and targeted PET imaging with scandium-44

Abstract

Scandium-44 has emerged as an attractive, novel PET radioisotope with ideal emission properties and half-life (<i>t</i> _1/2 = 3.97 h, <i>E</i> _mean 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^-1 and formation of inert <i>RRR</i>-Λ and <i>SSS</i>-Δ-twist isomers. Sc(picaga)-DUPA exhibits a <i>K</i> _i of 1.6 nM for PSMA, comparable to the ¹⁸F-based imaging probe DCFPyL (<i>K</i> _i = 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.