Issue 29, 2024

PYTA: a universal chelator for advancing the theranostic palette of nuclear medicine

Abstract

To clinically advance the growing arsenal of radiometals available to image and treat cancer, chelators with versatile binding properties are needed. Herein, we evaluated the ability of the py2[18]dieneN6 macrocycle PYTA to interchangeably bind and stabilize 225Ac3+, [177Lu]Lu3+, [111In]In3+ and [44Sc]Sc3+, a chemically diverse set of radionuclides that can be used complementarily for targeted alpha therapy, beta therapy, single-photon emission computed tomography (SPECT) imaging, and positron emission tomography (PET) imaging, respectively. Through NMR spectroscopy and X-ray diffraction, we show that PYTA possesses an unusual degree of flexibility for a macrocyclic chelator, undergoing dramatic conformational changes that enable it to optimally satisfy the disparate coordination properties of each metal ion. Subsequent radiolabeling studies revealed that PYTA quantitatively binds all 4 radiometals at room temperature in just minutes at pH 6. Furthermore, these complexes were found to be stable in human serum over 2 half-lives. These results surpass those obtained for 2 state-of-the-art chelators for nuclear medicine, DOTA and macropa. The stability of 225Ac–PYTA and [44Sc]Sc–PYTA, the complexes having the most disparity with respect to metal-ion size, was further probed in mice. The resulting PET images (44Sc) and ex vivo biodistribution profiles (44Sc and 225Ac) of the PYTA complexes differed dramatically from those of unchelated [44Sc]Sc3+ and 225Ac3+. These differences provide evidence that PYTA retains this size-divergent pair of radionuclides in vivo. Collectively, these studies establish PYTA as a new workhorse chelator for nuclear medicine and warrant its further investigation in targeted constructs.

Graphical abstract: PYTA: a universal chelator for advancing the theranostic palette of nuclear medicine

Supplementary files

Article information

Article type
Edge Article
Submitted
20 dec 2023
Accepted
05 jun 2024
First published
17 jun 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 11279-11286

PYTA: a universal chelator for advancing the theranostic palette of nuclear medicine

M. E. Simms, Z. Li, M. M. Sibley, A. S. Ivanov, C. M. Lara, T. C. Johnstone, V. Kertesz, A. Fears, F. D. White, D. L. J. Thorek and N. A. Thiele, Chem. Sci., 2024, 15, 11279 DOI: 10.1039/D3SC06854D

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