Advancing Chelation Strategies for Large Metal Ions for Nuclear Medicine Applications

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Nuclear 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 225 Ac 3+ , 132/135 La 3+ , 131 Ba 2+ , 223 Ra 2+ , 213 Bi 3+ , 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 mcpclick, 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 135 La 3+ , 225 Ac 3+ , 213 Bi 3+ , and small 44 Sc 3+ 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.

Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa

“…In this regard, we first evaluated the thermodynamic stability of Ln 3+ –py 2 -macrodipa complexes by determining their stability constants. The magnitude of the stability constant measures the thermodynamic affinity of a ligand for a metal ion and is valuable for assessing its potential in different applications. ,, The protonation constants ( K i ) of py 2 -macrodipa, as well as the stability constants ( K LnL ) of its Ln 3+ complexes, measured via either potentiometric titrations or ultraviolet–visible (UV–Vis) spectrophotometric titrations, − are collected in Table . These quantities are defined in eqs and , where the concentration terms represent those at chemical equilibrium and L signifies the uncomplexed ligand in its fully deprotonated state. The log K LnL values of py 2 -macrodipa, and those of the related structures macrodipa, py-macrodipa, and macropa, are plotted against the Ln 3+ 6-coordinate ionic radius in Figure .…”

“…The magnitude of the stability constant measures the thermodynamic affinity of a ligand for a metal ion and is valuable for assessing its potential in different applications. 10,25,26 The protonation constants (K i ) of py 2 -macrodipa, as well as the stability constants (K LnL ) of its Ln 3+ complexes, measured via either potentiometric titrations or ultraviolet− visible (UV−Vis) spectrophotometric titrations, 27−29 are collected in Table 1. These quantities are defined in eqs 2 and 3, where the concentration terms represent those at chemical equilibrium and L signifies the uncomplexed ligand in its fully deprotonated state.…”

“…Facile complex formation minimizes radioactivity loss during handling before in vivo administration, and high complex stability prevents in vivo release of the potentially harmful radiometal. A significant body of research has been devoted to chelator design for radiometals by addressing their distinct chemical properties and coordination chemistry preferences. − …”

“…This dual-size-selective property is attributed to a significant conformational toggle that occurs in this ligand class as they bind metal ions of different sizes (Scheme ) to optimize complex stability. For large Ln 3+ , a 10-coordinate, nearly C 2 -symmetric complex is formed (Conformation A), whereas for small Ln 3+ , an 8-coordinate asymmetric complex arises (Conformation B). − The first identified member of this ligand class was the macrocyclic chelator macrodipa (Chart ). Despite the unique selectivity profile of macrodipa, the kinetic lability of the corresponding Ln 3+ −macrodipa complexes limited its use for biomedical applications …”

Synthesis of Pincer type carbene and their Ag(I)-NHC complexes, and their Antimicrobial activities

“…Co-crystallization of a drug with another conformers greatly influences its physicochemical features, while it is hoped that metal complexes of theophylline will change the physiological structure of the drug by means of coordination bonds [33]. Alkali metal ions play a very important role in diverse biological subjects, such as within cellular diversity, pH, and tuning electrolyte balance [34][35][36]. In this study, it was proved that mono sodium salts possess a larger spectrum of antibacterial activity and they are effective especially against Staphylococcus Aureus, with over the range of pH 5.0 to 9.0 as bactericides.…”