Advancing Chelation Strategies for Large Metal Ions for Nuclear Medicine Applications

螯合作用 化学 配体(生物化学) 背景(考古学) 组合化学 纳米技术 有机化学 生物化学 材料科学 受体 古生物学 生物
作者
Aohan Hu,Justin J. Wilson
出处
期刊:Accounts of Chemical Research [American Chemical Society]
卷期号:55 (6): 904-915 被引量:39
标识
DOI:10.1021/acs.accounts.2c00003
摘要

ConspectusNuclear medicine leverages radioisotopes of a wide range of elements, a significant portion of which are metals, for the diagnosis and treatment of disease. To optimally use radioisotopes of the metal ions, or radiometals, for these applications, a chelator that efficiently forms thermodynamically and kinetically stable complexes with them is required. The chelator also needs to attach to a biological targeting vector that locates pathological tissues. Numerous chelators suitable for small radiometals have been established to date, but chelators that work well for large radiometals are significantly less common. In this Account, we describe recent progress by us and others in the advancement of ligands for large radiometal chelation with emerging applications in nuclear medicine.First, we discuss and analyze the coordination chemistry of the chelator macropa, a macrocyclic ligand that contains the 18-crown-6 backbone and two picolinate pendent arms, with large metal ions in the context of nuclear medicine. This ligand is known for its unusual reverse size selectivity, the preference for binding large over small metal ions. The radiolabeling properties of macropa with large radiometals 225Ac3+, 132/135La3+, 131Ba2+, 223Ra2+, 213Bi3+, and related in vivo investigations are described. The development of macropa derivatives containing different pendent donors or rigidifying groups in the macrocyclic core is also briefly reviewed.Next, efforts to transform macropa into a radiopharmaceutical agent via covalent conjugation to biological targeting vectors are summarized. In this discussion, two types of bifunctional analogues of macropa reported in the literature, macropa-NCS and mcp-click, are presented. Their implementation in different radiopharmaceutical agents is discussed. Bioconjugates containing macropa attached to small-molecule targeting vectors or macromolecular antibodies are presented. The in vitro and in vivo evaluations of these constructs are also discussed.Lastly, chelators with dual size selectivity are described. This class of ligands exhibits good affinities for both large and small metal ions. This property is valuable for nuclear medicine applications that require the simultaneous chelation of both large and small radiometals with complementary therapeutic and diagnostic properties. Recently, we reported an 18-membered macrocyclic ligand called macrodipa that attains this selectivity pattern. This chelator, its second-generation analogue py-macrodipa, and their applications for chelating the medicinally relevant large 135La3+, 225Ac3+, 213Bi3+, and small 44Sc3+ ions are also presented. Studies with these radiometals show that py-macrodipa can effectively radiolabel and stably retain both large and small radiometals. Overall, this Account makes the case for innovative ligand design approaches for novel emerging radiometal ions with unusual coordination chemistry properties.
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