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

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.