Positron emission tomography (PET) is a molecular imaging technology that can be used to detect various diseases including cancer. Zirconium... Show morePositron emission tomography (PET) is a molecular imaging technology that can be used to detect various diseases including cancer. Zirconium-89 (t1/2 = 78.4 h) is one of the positron-emitting radionuclides that has been widely explored for PET imaging because its half-life matches the long biological half-life of antibody. Research efforts have been devoted to the development of chelation chemistry for 89Zr, a bone-seeking radionuclide. Deferoxamine (DFO) is the most frequently used chelator for 89Zr in both clinical and preclinical trials. DFO can rapidly sequester 89Zr to form 89Zr-DFO complex. However, DFO is not an ideal ligand for 89Zr because 89Zr-labeled DFO-antibody conjugate showed high bone uptake in mice. We wanted to develop novel small molecule donors and novel chelators for 89Zr. We discovered N-methyl-N-(pyridin-2-yl)hydroxylamine (Py-HA) and 2,6-bis(N-methylhydroxylamino)pyridine (Py-BHA) as small molecule donors for 89Zr. Based on the new small molecule donors (Py-HA and Py-BHA), we have designed and synthesized a series of novel macrocyclic chelators containing TACN (1,4,7-triazacyclononane), CYCLEN (1,4,7,10-tetraazacyclododecane), and a diaza-crown ether backbone for 89Zr-based PET imaging applications. Moreover, bifunctional chelators (BFCs) structured on TACN and diaza-18-crown-6 were synthesized for conjugation to antibody. Theranostics contains a diagnostic agent and a therapeutic drug that can be used for simultaneous therapy and imaging of diseases. Radiotheranostics includes radiometal complexes for both therapy and imaging. 177Lu is a promising radiotheranostic metal because it can emit gamma radiation for single photon emission computed tomography (SPECT) imaging and emit β radiation for radiotherapy. A radioisotope pair with complementary emission such as 64Cu/67Cu and 86Y/90Y, can be used for PET imaging and radiotherapy. In this study, we synthesized nonfunctional TACN and diaza crown ether-backboned chelators containing different donor groups for 177Lu, 64Cu/67Cu, and 86Y/90Y. Finally, two bifunctional chelators were synthesized for coupling with hydroxamic acid-based small molecule as a potential histone deacetylase (HDAC) inhibitor to generate a small molecule ligand-chelator conjugate (SMLC) for theranostic applications. Show less
