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Issue 2, 2020
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Chelation with a twist: a bifunctional chelator to enable room temperature radiolabeling and targeted PET imaging with scandium-44

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Abstract

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−1 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.

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

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Supplementary files

Article information


Submitted
14 Sep 2019
Accepted
17 Nov 2019
First published
20 Nov 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 333-342
Article type
Edge Article

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

B. A. Vaughn, S. H. Ahn, E. Aluicio-Sarduy, J. Devaraj, A. P. Olson, J. Engle and E. Boros, Chem. Sci., 2020, 11, 333
DOI: 10.1039/C9SC04655K

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