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 py 2 [18]dieneN 6 macrocycle PYTA to interchangeably bind and stabilize 225 Ac 3+ , [ 177 Lu]Lu 3+ , [ 111 In]In 3+ and [ 44 Sc]Sc 3+ , 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 225 Ac-PYTA and [ 44 Sc]Sc-PYTA, the complexes having the most disparity with respect to metal-ion size, was further probed in mice. The resulting PET images ( 44 Sc) and ex vivo biodistribution profiles ( 44 Sc and 225 Ac) of the PYTA complexes differed dramatically from those of unchelated [ 44 Sc]Sc 3+ and 225 Ac 3+ . 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. PYTA is demonstrated to rapidly and stably complex 225 Ac, 177 Lu, 111 In, and 44 Sc, a "superfecta" of complementary but chemically distinct radiometals for targeted theranostic applications.