10 research outputs found
Alternative Chelator for 89Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)
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
Reduced cortical thickness in World Trade Center responders with cognitive impairment
This study examined cortical thickness (CTX) in World Trade Center (WTC) responders with cognitive impairment (CI)
Alternative Chelator for <sup>89</sup>Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)
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
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
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
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
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
Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility