Chelating the Alpha Therapy Radionuclides 225Ac3+ and 213Bi3+ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

Hu, Aohan; Brown, Victoria; MacMillan, Samantha N.; Radchenko, Valery; Yang, Hua; Wharton, Luke; Ramogida, Caterina F.; Wilson, Justin J.

doi:10.1021/acs.inorgchem.1c03670

Cited by 20 publications

(29 citation statements)

References 60 publications

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“…Notably, py 2 -macrodipa quantitatively incorporates 225 Ac 3+ at a low concentration of 10 –5 M within 5 min, revealing it to be an efficient chelator for 225 Ac 3+ . This property is nearly on par with that of macropa, the current gold standard, which quantitatively radiolabels 225 Ac 3+ at micromolar concentration, an observation consistent with previously reported results. , By contrast, DOTA did not significantly undergo 225 Ac 3+ radiolabeling even at a millimolar concentration. Increasing the reaction time to 60 min had only a slight effect on the RCYs for py 2 -macrodipa and macropa, indicating that the radiolabeling process is nearly complete within 5 min under these mild conditions for both chelators.…”

Section: Resultssupporting

confidence: 91%

“…Based on these improvements of macrodipa, we showed that py-macrodipa efficiently formed stable complexes with 135 La 3+ and 44 Sc 3+ , two valuable radionuclides for nuclear medicine with significantly disparate ionic radii . To further validate the potential of py-macrodipa for nuclear medicine applications, we assessed its suitability for chelating 225 Ac 3+ and 213 Bi 3+ , two therapeutically valuable α-emitters. , These studies showed that py-macrodipa is a promising candidate for 213 Bi 3+ chelation but does not form a complex of sufficient kinetic stability for 225 Ac 3+ nuclear medicine applications …”

Section: Introductionmentioning

confidence: 99%

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

Simms

Kertész

et al. 2022

Inorg. Chem.

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Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal–ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln3+), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for 135La3+, 213Bi3+, and 44Sc3+ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py2-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln3+ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py2-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln3+ compared to py-macrodipa. By contrast, the kinetic stability of Ln3+ complexes with py2-macrodipa is only improved for the light, large Ln3+ ions. Based upon these observations, we further assessed the suitability of py2-macrodipa for use with 225Ac3+, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py2-macrodipa to efficiently incorporate 225Ac3+ and to form a complex that is inert in human serum over 3 weeks. Although py2-macrodipa does not surpass the state-of-the-art chelator macropa for 225Ac3+ chelation, it does provide another effective 225Ac3+ chelator. These studies shed light on the fundamental coordination chemistry of the Ln3+ series and may inspire future chelator design efforts.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Simms

Kertész

et al. 2022

Inorg. Chem.

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“…Even though the pymacrodipa complex with Ac 3+ is kinetically labile and not optimal for nuclear medicine purposes, the Bi 3+ complex has remarkable kinetic stability, surpassing that of macropa. 70 This study established py-macrodipa as a promising candidate for 213 Bi 3+ chelation, representing an extension of its versatility for a wide range of metal ions.…”

Section: Stable Chelation For Both the Large And Small Metal Ions: Th...mentioning

confidence: 93%

“…On the basis of the success of py-macrodipa with 135 La 3+ and 44 Sc 3+ , we next employed this system for other non-Ln 3+ radiometals such as large α-emitting radiometals 225 Ac 3+ and 213 Bi 3+ . Despite the nearly identical ionic radii of La 3+ and Bi 3+ , 28 the Bi 3+ complex of py-macrodipa adopts asymmetric Conformation B, 70 which is normally preferred for small ions. This unexpected geometry is possibly a consequence of the stereochemical activity of the Bi 3+ 6s 2 lone pair.…”

Section: Stable Chelation For Both the Large And Small Metal Ions: Th...mentioning

confidence: 99%

Advancing Chelation Strategies for Large Metal Ions for Nuclear Medicine Applications

Wilson

2022

Acc. Chem. Res.

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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.

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“…The lack of stability is likely a product of both small ring size and the distance between the metal ion and the oxygen donor atoms of the acetic acid pendant arms [224] . To address these limitations, larger 18-membered macrocycles such as macropa [183] , crown [225] , py-macrodipa [226] , and mcp-D-click [227] have recently been introduced to chelate 225 Ac 3+ or 213 Bi 3+ with exceptionally high stability. An alternative approach has been to explore acyclic hydroxypyridinonate (HOPO) or picolinic acid chelators.…”

Section: Introductionmentioning

confidence: 99%

Advances in PSMA theranostics

Jeitner

Babich

Kelly

2022

Translational Oncology

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Chelating the Alpha Therapy Radionuclides ²²⁵Ac³⁺ and ²¹³Bi³⁺ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

Cited by 20 publications

References 60 publications

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

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

Advancing Chelation Strategies for Large Metal Ions for Nuclear Medicine Applications

Advances in PSMA theranostics

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Chelating the Alpha Therapy Radionuclides 225Ac3+ and 213Bi3+ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

Cited by 20 publications

References 60 publications

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

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

Advancing Chelation Strategies for Large Metal Ions for Nuclear Medicine Applications

Advances in PSMA theranostics

Contact Info

Product

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Chelating the Alpha Therapy Radionuclides ²²⁵Ac³⁺ and ²¹³Bi³⁺ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

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

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