Design of a multivalent bifunctional chelator for diagnostic 64Cu PET imaging in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Cho HJ
PROVIDER: S-EPMC7733815 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Self-illuminating fluorescence imaging without autofluorescence background interference has recently aroused more research interests in molecular imaging. Currently, only a few self-illuminating probes were developed, based mainly on toxic quantum dots such as CdSe, CdTe. Herein, we report a novel design of nontoxic self-illuminating gold nanocluster ((64)Cu-doped AuNCs) for dual-modality positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging based on Cerenkov resonance energy transfer (CRET). PET radionuclide (64)Cu was introduced by a chelator-free doping method, which played dual roles as the energy donor and the PET imaging source. Meanwhile, AuNCs acted as the energy acceptor for NIR fluorescence imaging. (64)Cu-doped AuNCs exhibited efficient CRET-NIR and PET imaging both in vitro and in vivo. In a U87MG glioblastoma xenograft model, (64)Cu-doped AuNCs showed high tumor uptake (14.9 %ID/g at 18 h) and produced satisfactory tumor self-illuminating NIR images in the absence of external excitation. This self-illuminating nanocluster with non-toxicity and good biocompatibility can be employed as a novel imaging contrast agent for biomedical applications, especially for molecular imaging.
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Project description:Bifunctional chelators as parts of modular metal-based radiopharmaceuticals are responsible for stable complexation of the radiometal ion and for covalent linkage between the complex and the targeting vector. To avoid loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups. The C9 position of the very stable CuII chelator 3,7-diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisation does not disturb the metal binding centre. We describe the preparation and characterisation of a set of novel bispidine derivatives equipped with suitable functional groups for diverse bioconjugation reactions, including common amine coupling strategies (bispidine-isothiocyanate) and the Cu-free strain-promoted alkyne-azide cycloaddition. We demonstrate their functionality and versatility in an exemplary way by conjugation to an antibody-based biomolecule and validate the obtained conjugate in vitro and in vivo.
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Project description:PurposeThis study presents the biodistribution, clearance and dosimetry estimates of [64Cu]Fibrin Binding Probe #8 ([64Cu]FBP8) in healthy subjects.ProceduresThis prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [64Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 hours, 4h and 24h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software.ResultsSubjects were injected with ~400 MBq of [64Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [64Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67 min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [18F]fluorodeoxyglucose ([18F]FDG, 0.020mSv/MBq).ConclusionsThis study demonstrates the following properties of the [64Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20 minutes in a single session. These properties provide the basis for [64Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions.
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Project description:PurposeThe aim of this study was to assess and compare the arterial uptake of the inflammatory macrophage targeting PET tracer [64Cu]Cu-DOTATATE in patients with no or known cardiovascular disease (CVD) to investigate potential differences in uptake.MethodsSeventy-nine patients who had undergone [64Cu]Cu-DOTATATE PET/CT imaging for neuroendocrine neoplasm disease were retrospectively allocated to three groups: controls with no known CVD risk factors (n = 22), patients with CVD risk factors (n = 24), or patients with known ischemic CVD (n = 33). Both maximum, mean of max and most-diseased segment (mds) standardized uptake value (SUV) and target-to-background ratio (TBR) uptake metrics were measured and reported for the carotid arteries and the aorta. To assess reproducibility between different reviewers, Bland-Altman plots were made.ResultsFor the carotid arteries, SUVmax (P = .03), SUVmds (0.05), TBRmax (P < .01), TBRmds (P < .01), and mean-of-max TBR (P = .01) were overall shown to provide a group-wise difference in uptake. When measuring uptake values in the aorta, a group-wise difference was only observed with TBRmds (P = .04). Overall, reproducibility of the reported uptake metrics was excellent for SUVs and good to excellent for TBRs for both the carotid arteries and the aorta.ConclusionUsing [64Cu]Cu-DOTATATE PET imaging as a marker of atherosclerotic inflammation, we were able to demonstrate differences in some of the most frequently reported uptake metrics in patients with different degrees of CVD. Measurements of the carotid artery as either maximum uptake values or most-diseased segment analysis showed the best ability to discriminate between the groups.
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Project description:PurposeAll clinical 89Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of 89Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its 89Zr-DFO*-mAb complex with 89Zr-DFO-mAb.MethodsThe bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging.ResultsIn 0.9 % NaCl 89Zr-DFO*-trastuzumab was more stable than 89Zr-DFO-trastuzumab; after 72 h incubation at 2-8 °C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were???92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59?±?11.95 and 29.06?±?8.66 % ID/g for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for 89Zr-DFO*-trastuzumab compared to 89Zr-DFO-trastuzumab. At 144 h p.i. for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, the uptake in sternum was 0.92?±?0.16 and 3.33?±?0.32 % ID/g, in femur 0.78?±?0.11 and 3.85,?±?0.80 and in knee 1.38?±?0.23 and 8.20?±?2.94 % ID/g, respectively. The uptake in bone decreased from 24 h to 144 h p.i. about two fold for the DFO* conjugate, while it increased about two fold for the DFO conjugate.ConclusionsZr-DFO*-trastuzumab showed superior in vitro stability and in vivo performance when compared to 89Zr-DFO-trastuzumab. This makes the new octadentate DFO* chelator a candidate successor of DFO for future clinical 89Zr-immuno-PET.
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Project description:The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64Cu-DOTA-alendronate. Results:64Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion:64Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as the differentiation of malignant versus benign tumors based on absolute labeling uptake.
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Project description:Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aβ) peptide aggregates in the brain of Alzheimer's disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides 11C (20.4 min) and 18F (109.8 min) may limit the widespread use of these imaging agents. Therefore, we have begun to evaluate novel AD diagnostic agents that can be radiolabeled with 64Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L1-L5, that were designed to tightly bind 64Cu and shown to interact with Aβ aggregates both in vitro and in transgenic AD mouse brain sections. Importantly, biodistribution studies show that these compounds exhibit promising brain uptake and rapid clearance in wild-type mice, and initial microPET imaging studies of transgenic AD mice suggest that these compounds could serve as lead compounds for the development of improved diagnostic agents for AD.
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Project description:Vascular endothelial growth factor receptors (VEGFRs) are well recognized as significant biomarkers of tumor angiogenesis. Herein, we have developed a first-of-its-kind peptide-based VEGFR positron emission tomography (PET) tracer. The novel [64Cu]VEGF125-136 peptide possessed satisfactory radio-characteristics and showed good specificity for the visualization of VEGFR in various mouse models, in which the tumor-specific radioactivity uptake was highly correlated to the VEGFR expression level. Moreover, the tracer showed high tumor uptake (ca. 5.89 %ID/g at 20 min postinjection in B16F10 mice) and excellent pharmacokinetics, achieving the maximum imaging quality within 1 h after injection. These features convey [64Cu]VEGF125-136 as a promising, clinically translatable PET tracer for the imaging of tumor angiogenesis.
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Project description:PurposeGlioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET.Experimental designWe generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells.ResultsNontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors.ConclusionsHuman CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.
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