10 research outputs found

    Alternative Chelator for 89Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)

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    Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of mice suggests that 89Zr4+ is released from DFO in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of 89Zr-HOPO matched or surpassed that of 89Zr-DFO in every experiment. In healthy mice, 89Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for 89Zr-based PET imaging agents

    Alternative Chelator for <sup>89</sup>Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)

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    Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for <sup>89</sup>Zr<sup>4+</sup>; however, accumulation of <sup>89</sup>Zr in the bones of mice suggests that <sup>89</sup>Zr<sup>4+</sup> is released from DFO in vivo. An improved chelator for <sup>89</sup>Zr<sup>4+</sup> could eliminate the release of osteophilic <sup>89</sup>Zr<sup>4+</sup> and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of <sup>89</sup>Zr-HOPO matched or surpassed that of <sup>89</sup>Zr-DFO in every experiment. In healthy mice, <sup>89</sup>Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for <sup>89</sup>Zr-based PET imaging agents

    Selective hippocampal subfield volume reductions in World Trade Center responders with cognitive impairment

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    Introduction The objective of this study was to investigate associations between dementia in World Trade Center (WTC) responders and in vivo volumetric measures of hippocampal subfield volumes in WTC responders at midlife.Methods A sample of 99 WTC responders was divided into dementia and unimpaired groups. Participants underwent structural T1-weighted magnetic resonance imaging. Volumetric measures included the overall hippocampus and eight subfields. Regression models examined volumetric measure of interest adjusting for confounders including intracranial volume.Results Dementia was associated with smaller hippocampal volume and with reductions across hippocampal subfields. Smaller hippocampal subfield volumes were associated with longer cumulative time worked at the WTC. Domain-specific cognitive performance was associated with lower volumetric measures across hippocampal subregions.Conclusions This is the first study to investigate hippocampal subfield volumes in a sample of WTC responders at midlife. Selective hippocampal subfield volume reductions suggested abnormal cognition that were associated with WTC exposure duration

    <i>p</i>‑SCN-Bn-HOPO: A Superior Bifunctional Chelator for <sup>89</sup>Zr ImmunoPET

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    Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the <sup>89</sup>Zr<sup>4+</sup> cation is being released in vivo. Therefore, a more robust chelator for <sup>89</sup>Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of <sup>89</sup>Zr<sup>4+</sup> and high stability; therefore, we developed a bifunctional derivative, <i>p</i>-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. <i>p</i>-SCN-Bn-HOPO was synthesized through a novel pathway. Both <i>p</i>-SCN-Bn-HOPO and <i>p</i>-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with <sup>89</sup>Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (<i>n</i> = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the <sup>89</sup>Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for <sup>89</sup>Zr-DFO-trastuzumab while <sup>89</sup>Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized <i>p</i>-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for <sup>89</sup>Zr. In vivo studies demonstrate the successful use of <sup>89</sup>Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with <sup>89</sup>Zr-HOPO-trastuzumab suggests superior stability of the <sup>89</sup>Zr-HOPO complex

    Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals

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    Three isotopes of scandium43Sc, 44Sc, and 47Schave attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals

    Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals

    No full text
    Three isotopes of scandium43Sc, 44Sc, and 47Schave attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals
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