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PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation
摘要： Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [18F]JNJ-64413739 has been recently disclosed. Procedures: We evaluated [18F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [18F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446. Results: Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [18F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [18F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels. Conclusions: While further work is needed to study [18F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [18F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.
关键词： Lipopolysaccharide,Rats,Positron emission tomography (PET),PET imaging,P2X7 receptor,LPS,[18F]JNJ-64413739,Neuroinflammation
更新于2025-09-23 15:22:29
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Preclinical evaluation of [ <sup>18</sup> F]MA3, a CB <sub/>2</sub> receptor agonist radiotracer for Positron Emission Tomography
摘要： Background and Purpose: Non-invasive in vivo imaging of CB2 receptors (CB2R) using positron emission tomography (PET) is pursued to study neuroinflammation. The purpose of this study is to evaluate the in vivo binding specificity of [18F]MA3, a CB2R agonist, in a rat model with local overexpression of human CB2R (hCB2R). Methods: [18F]MA3 was produced with good radiochemical yield and radiochemical purity. The radiotracer was evaluated in rats with local overexpression of hCB2R and in a healthy non-human primate using PET. Key results: Ex vivo autoradiography demonstrated CB2 specific binding of [18F]MA3 in rat hCB2R vector injected striatum. In a PET study, increased tracer binding in the hCB2R vector injected striatum compared to the contralateral control vector injected striatum was observed. Binding in hCB2R vector injected striatum was blocked with a structurally non related CB2R inverse agonist and a displacement study confirmed the reversibility of tracer binding. This study identified the utility of mutated inactive vector model for evaluation of CB2R agonist PET tracers. [18F]MA3 PET scans in the non-human primate showed good uptake and fast wash out from brain, but no CB2 specific binding was observed. Conclusion and Implications: Evaluation of [18F]MA3 in a rat model with local overexpression of hCB2R showed CB2 specific and reversible tracer binding. [18F]MA3 showed good brain uptake and subsequent wash out in a healthy non-human primate but no specific binding was observed. Further clinical evaluation of [18F]MA3 in patients with neuroinflammation is warranted.
关键词： CB2R,PET imaging,neuroinflammation,[18F]MA3,radiotracer
更新于2025-09-23 15:22:29
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Evaluation of [ <sup>11</sup> C]NMS-E973 as a PET tracer for <i>in vivo</i> visualisation of HSP90
摘要： Heat shock protein 90 is an ATP-dependent molecular chaperone important for folding, maturation and clearance of aberrantly expressed proteins and is abundantly expressed (1-2% of all proteins) in the cytosol of all normal cells. In some tumour cells, however, strong expression of HSP90 is also observed on the cell membrane and in the extracellular matrix and the affinity of tumoural HSP90 for ATP domain inhibitors was reported to increase over 100-fold compared to that of HSP90 in normal cells. Here, we explore [11C]NMS-E973 as a PET tracer for in vivo visualisation of HSP90 and as a potential tool for in vivo quantification of occupancy of HSP90 inhibitors. Methods: HSP90 expression was biochemically characterized in a panel of established cell lines including the melanoma line B16.F10. B16.F10 melanoma xenograft tumour tissue was compared to non-malignant mouse tissue. NMS-E973 was tested in vitro for HSP90 inhibitory activity in several tumour cell lines. HSP90-specific binding of [11C]NMS-E973 was evaluated in B16.F10 melanoma cells and B16.F10 melanoma, prostate cancer LNCaP and PC3, SKOV-3 xenograft tumour slices and in vivo in a B16.F10 melanoma mouse model. Results: Strong intracellular upregulation and abundant membrane localisation of HSP90 was observed in the different tumour cell lines, in the B16.F10 tumour cell line and in B16.F10 xenograft tumours compared to non-malignant tissue. NMS-E973 showed HSP90-specific inhibition and reduced proliferation of cells. [11C]NMS-E973 showed strong binding to B16.F10 melanoma cells, which was inhibited by 200 μM of PU-H71, a non-structurally related HSP90 inhibitor. HSP90-specific binding was observed by in vitro autoradiography of murine B16.F10 melanoma, LNCaP and PC3 prostate cancer and SKOV-3 ovary carcinoma tissue slices. Further, B16.F10 melanoma-inoculated mice were subjected to a μPET study, where the tracer showed fast and persistent tumour uptake. Pretreatment of B16.F10 melanoma mice with PU-H71 or Ganetespib (50 mg/kg) completely blocked tumour accumulation of [11C]NMS-E973 and confirmed in vivo HSP90 binding specificity. HSP90-specific binding of [11C]NMS-E973 was observed in blood, lungs and spleen of tumour-bearing animals but not in control animals. Conclusion: [11C]NMS-E973 is a PET tracer for in vivo visualisation of tumour HSP90 expression and can potentially be used for quantification of HSP90 occupancy. Further translational evaluation of [11C]NMS-E973 is warranted.
关键词： HSP90,melanoma,PET imaging,carbon-11,NMS-E973
更新于2025-09-23 15:22:29
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Synthesis and preclinical evaluation of 68Ga-PSMA-BCH for prostate cancer imaging
摘要： Prostate specific membrane antigen (PSMA) is a promising target for the diagnosis and therapy of prostate cancer. In this report, a NOTA-conjugated precursor, NOTA-PSMA (also named PSMA-BCH), was synthesized by peptide synthesizer with the chemical purity over 95%. 68Ga-PSMA-BCH was obtained by radiolabeling NOTA-PSMA with 68GaCl3 with >99% radiochemical purity and 59-74 GBq/μmol specific activity. In vitro and in vivo study of 68Ga-PSMA-BCH showed high stability, high uptake in PSMA-expressing cells and tumor, fast clearance and low non-target uptake. 22Rv1 tumors were clearly observed in micro-PET images of and showed good retention. Compared with 68Ga-PSMA-617, 68Ga-PSMA-BCH showed comparable tumor uptake and tumor-background ratios. Indicating 68Ga-PSMA-BCH is a promising candidate for prostate cancer imaging and worthy of further clinical investigations.
关键词： 68Ga-PSMA-BCH,PSMA,PET imaging,Prostate cancer
更新于2025-09-23 15:22:29
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Preclinical Evaluation of a Novel <sup>18</sup> F-Labeled dTCO-Amide Derivative for Bioorthogonal Pretargeted Positron Emission Tomography Imaging
摘要： Pretargeted positron emission tomography (PET) imaging based on the bioorthogonal inverse-electron-demand Diels?Alder reaction between tetrazines (Tz) and trans-cyclooctenes (TCO) has emerged as a promising tool for solid tumor imaging, allowing the use of short-lived radionuclides in immune-PET applications. With this strategy, it became possible to achieve desirable target-to-background ratios and at the same time to decrease the radiation burden to nontargeted tissues because of the fast clearance of small PET probes. Here, we show the synthesis of novel 18F-labeled dTCO-amide probes for pretargeted immuno-PET imaging. The PET probes were evaluated regarding their stability, reactivity toward tetrazine, and pharmacokinetic pro?le. [18F]MICA-213 showed an extremely fast kinetic rate (10,553 M?1 s?1 in 50:50 MeOH/water), good stability in saline and plasma up to 4 h at 37 °C with no isomerization observed, and the biodistribution in healthy mice revealed a mixed hepatobiliary and renal clearance with no de?uorination and low background in other tissues. [18F]MICA-213 was further used for in vivo pretargeted immune-PET imaging carried out in nude mice bearing LS174T colorectal tumors that were previously treated with a tetrazine-modi?ed anti-TAG-72 monoclonal antibody (CC49). Pretargeted μPET imaging results showed clear visualization of the tumor tissue with a signi?cantly higher uptake when compared to the control.
关键词： immuno-PET,tetrazines,bioorthogonal chemistry,Pretargeted PET imaging,trans-cyclooctenes
更新于2025-09-23 15:21:01
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Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature
摘要： Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of PD-1/PD-L1 blockade. A CD276-targeting agent (IRD-αCD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting and therapeutic effect of IRD-αCD276/Fab with or without anti-PD-1/PD-L1 blockade was tested in subcutaneous and lung metastatic tumor models. PDT using IRD-αCD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD-L1 levels were also markedly increased after PDT using IRD-αCD276/Fab, as evidenced by noninvasive PD-L1-targeted small-animal PET imaging. In combination with anti-PD-1/PD-L1 blockade, IRD-αCD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8+ T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD-1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses.
关键词： Molecular imaging,Checkpoint inhibition,Photoimmunotherapy,PET imaging,Angiogenesis
更新于2025-09-23 15:21:01
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[IEEE 2018 IEEE 38th International Conference on Electronics and Nanotechnology (ELNANO) - Kiev (2018.4.24-2018.4.26)] 2018 IEEE 38th International Conference on Electronics and Nanotechnology (ELNANO) - Florbetapir Image Analysis for Alzheimer's Disease Diagnosis
摘要： Over decades Alzheimer’s disease (AD) remains without decent cure, and only disease-modifying methods are available. This paper is devoted to the analysis of amyloid-PET images with florbetapir (18F-AV-45) tracer to detect the presence of AD or Mild Cognitive Impairment (MCI). The first part of the article dedicated to image processing pipeline, specifically, spacial normalisation and feature extraction. The second part is devoted to the development of the multiclass classifier with deep learning methods. In particular, deep neural network was developed to distinguish three stages: health control (HC), MCI and AD. After tuning and training a neural network, the final specificity of 78% and sensitivity of 90% has been achieved.
关键词： Deep learning,Florbetapir,PET imaging,Alzheimer's disease,Amyloid Imaging
更新于2025-09-19 17:15:36
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Fluorine-18 click radiosynthesis and MicroPET/CT evaluation of a small peptide-a potential PET probe for carbonic anhydrase IX
摘要： Carbonic anhydrase IX (CA IX) is the first carbonic anhydrase found to be associated with cancer that is over-expressed in a variety of human solid tumors. As a surrogate marker for hypoxia, the expression of CA IX is strongly upregulated in hypoxic tumors by hypoxia and hypoxia-inducible factor 1a (HIF-1a). In our pursuit of a CA IX-specific PET probe, we designed and synthesized a peptide-based CA IX imaging probe by the efficient click reaction of 1,3-dipolar cycloaddition of terminal alkynes and organic azides. The probe 18F-CA IX-P1-4-10 was obtained with a radiochemical yield of 35-45% (n = 5) and radiochemical purity of >99% in 70-80 min (HPLC purification time included). 18F-CAIX-P1-4-10 had good stability in phosphate buffered saline (PBS), but about 51% peptide degradation was detected in new-born calf serum (NBCS) after incubation. Preliminary microPET/CT experiments demonstrated a specific uptake of 18F-CA IX-P1-4-10 in HT29 tumor and the uptake of 18F-CA IX-P1-4-10 was blocked by peptide CA IX-P1-4-10-Yne pretreatment. Immunohistochemical staining and western blotting studies confirmed the HT29 tumor was CA IX-positive which further proved tumor accumulation of 18F-CA IX-P1-4-10 was correlated with CA IX expression. The results suggest that 18F-CA IX-P1-4-10 is a promising PET tracer for the specific imaging of CA IX-expressing tumors at the molecular level.
关键词： peptide,tumor hypoxia,18F-labeling,Carbonic anhydrase IX,PET imaging
更新于2025-09-19 17:15:36
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Synthesis and Preliminary Evaluations of a Triazole-cored Antagonist ([18F]N2B-0518) as PET Imaging Probe for GluN2B Subunit in the Brain
摘要： GluN2B is the most studied subunit of N-methyl-D-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified. Herein we developed an 18F-labeled potent antagonist, 2-((1-(4-[18F]fluoro-3-methylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxypyrimidine ([18F]13; also called [18F]N2B-0518) as a PET tracer for imaging the GluN2B subunit. The radiofluorination of [18F]13 was efficiently achieved by our spirocyclic iodonium ylide (SCIDY) method. In in vitro autoradiography studies, [18F]13 displayed highly region-specific binding in brain sections of rat and non-human primate, which was in accordance with the expression of GluN2B subunit. Ex vivo biodistribution in mice revealed that [18F]13 could penetrate the blood-brain barrier with moderate brain uptake (3.60% ID/g at 2 min) and rapid washout. Altogether, this work provides a GluN2B-selective PET tracer bearing new chemical scaffold and shows high specificity to GluN2B subunit in vitro, which may pave the way for the development of a new generation of GluN2B PET ligands.
关键词： subtype-selective,PET imaging,18F-labeling,autoradiography,GluN2B subunit,spirocyclic iodonium ylide
更新于2025-09-19 17:15:36
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[IEEE 2019 IEEE 46th Photovoltaic Specialists Conference (PVSC) - Chicago, IL, USA (2019.6.16-2019.6.21)] 2019 IEEE 46th Photovoltaic Specialists Conference (PVSC) - Micro-Transfer Printer-Assembled Five Junction CPV Microcell Development
摘要： Quantitative analysis of positron emission tomography (PET) brain imaging data requires a metabolite-corrected arterial input function (AIF) for estimation of distribution volume and related outcome measures. Collecting arterial blood samples adds risk, cost, measurement error, and patient discomfort to PET studies. Minimally invasive AIF estimation is possible with simultaneous estimation (SIME), but at least one arterial blood sample is necessary. In this study, we describe a noninvasive SIME (nSIME) approach that utilizes a pharmacokinetic input function model and constraints derived from machine learning applied to an electronic health record database consisting of “long tail” data (digital records, paper charts, and handwritten notes) that were collected ancillary to the PET studies. We evaluated the performance of nSIME on 95 [11C]DASB PET scans that had measured AIFs. The results indicate that nSIME is a promising alternative to invasive AIF measurement. The general framework presented here may be expanded to other metabolized radioligands, potentially enabling quantitative analysis of PET studies without blood sampling. A glossary of technical abbreviations is provided at the end of this paper.
关键词： Arterial input function (AIF),positron emission tomography (PET) imaging,electronic health record (EHR)
更新于2025-09-19 17:13:59