Dataset Information

Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [⁶⁸Ga]Ga-TC3-OGDOTA.

ABSTRACT: Apoptosis is a feature of stroke and Alzheimer's disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [⁶⁸Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and ⁶⁸Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [⁶⁸Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA labeled apoptotic neurons following exposure to camptothecin, oxygen-glucose deprivation, and β-amyloid oligomers. In vivo, PET showed accumulation of [⁶⁸Ga]Ga-TC3-OGDOTA in the brain of mouse models of stroke or AD. Optical clearing revealed colocalization of [⁶⁸Ga]Ga-TC3-OGDOTA and cleaved caspase-3 in brain cells. In stroke, [⁶⁸Ga]Ga-TC3-OGDOTA accumulated in neurons in the penumbra area, whereas in AD mice [⁶⁸Ga]Ga-TC3-OGDOTA was found in single cells in the forebrain and diffusely around amyloid plaques. In summary, this bifunctional tracer is selectively associated with apoptotic cells in vitro and in vivo in brain disease models and represents a novel tool for apoptosis detection that can be used in neurodegenerative diseases.

SUBMITTER: Ostapchenko VG

PROVIDER: S-EPMC6348924 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA.

Ostapchenko Valeriy G VG Snir Jonatan J Suchy Mojmir M Fan Jue J Cobb M Rebecca MR Chronik Blaine A BA Kovacs Michael M Prado Vania F VF Hudson Robert H E RHE Hudson Robert H E RHE Pasternak Stephen H SH Prado Marco A M MAM Bartha Robert R

Contrast media & molecular imaging 20190114

Apoptosis is a feature of stroke and Alzheimer's disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [68Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and 68Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [68Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA ...[more]

PMID: 30755766

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Project description:Background[68Ga]Ga-NeoB is a novel DOTA-coupled Gastrin Releasing Peptide Receptor (GRPR) antagonist with high affinity for GRPR and good in vivo stability. This study aimed at (1) the translation of preclinical results to the clinics and establish the preparation of [68Ga]Ga-NeoB using a GMP conform kit approach and a licensed 68Ge/68Ga generator and (2) to explore the application of [68Ga]Ga-NeoB in patients with gastrointestinal stromal tumors (GIST) before and/or after interventional treatment (selective internal radiotherapy, irreversible electroporation, microwave ablation).ResultsValidation of the production and quality control of [68Ga]Ga-NeoB for patient use had to be performed before starting the GMP production. Six independent batches of [68Ga]Ga-NeoB were produced, all met the quality and sterility criteria and yielded 712 ± 73 MBq of the radiotracer in a radiochemical purity of > 95% and a molar activity of 14.2 ± 1.5 GBq/μmol within 20 min synthesis time and additional 20 min quality control. Three patients (2 females, 1 male, 51-77 yrs. of age) with progressive gastrointestinal stromal tumor metastases in the liver or peritoneum not responsive to standard tyrosine kinase inhibitor therapy underwent both [68Ga]Ga-NeoB scans prior and after interventional therapy. Radiosynthesis of 68Ga-NeoB was performed using a kit approach under GMP conditions. No specific patient preparation such as fasting or hydration was required for [68Ga]Ga-NeoB PET/CT imaging. Contrast-enhanced PET/CT studies were performed. A delayed, second abdominal image after the administration of the of [68Ga]Ga-NeoB was acquired at 120 min post injection.ConclusionsA fully GMP compliant kit preparation of [68Ga]Ga-NeoB enabling the routine production of the tracer under GMP conditions was established for clinical routine PET/CT imaging of patients with metastatic GIST and proved to adequately visualize tumor deposits in the abdomen expressing GRPR. Patients could benefit from additional information derived from [68Ga]Ga-NeoB diagnosis to assess the presence of GRPR in the tumor tissue and monitor antitumor treatment.

Project description:ContextIn December 2020, the US Food and Drug Administration approved a 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA-11) for positron emission tomography (PET) in patients with suspected prostate cancer (PCa) metastasis who are candidates for initial definitive therapy. 68Ga-PSMA PET is increasingly performed for these patients and is usually combined with computed tomography (CT). In recent years, 68Ga-PSMA PET has been combined with high-resolution magnetic resonance imaging (MRI), which is beneficial for T staging and may further enhance the staging of primary PCa.ObjectiveTo compare the diagnostic accuracy of 68Ga-PSMA PET/MRI with 68Ga-PSMA PET/CT for staging of primary PCa.Evidence acquisitionA comprehensive literature search was performed using Embase, PubMed/Medline, Web of Science, Cochrane Library, and Google Scholar up to June 24, 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias was assessed using the QUADAS-2 tool.Evidence synthesisThe search identified 2632 articles, of which 27 were included. The diagnostic accuracy of 68Ga-PSMA PET/MRI, measured as the pooled natural logarithm of diagnostic odds ratio (lnDOR), was 2.27 (95% confidence interval [CI] 1.21-3.32) for detection of extracapsular extension (ECE), 3.50 (95% CI 2.14-4.86) for seminal vesicle invasion (SVI), and 4.73 (95% CI 2.93-6.52) for lymph node metastasis (LNM). For 68Ga-PSMA PET/CT, the analysis showed lnDOR of 2.45 (95% CI 0.75-4.14), 2.94 (95% CI 2.26-3.63), and 2.42 (95% CI 2.07-2.78) for detection of ECE, SVI, and LNM, respectively. The overall risk of bias and applicability concerns were assessed as moderate and low, respectively.Conclusions68Ga-PSMA PET/MRI shows high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/CT for detection of ECE, SVI, and LNM in staging of PCa. There is an urgent need for direct comparison of the two diagnostic tests in future research.Patient summaryThe use of radioactively labeled molecules that bind to prostate-specific membrane antigen (68Ga-PSMA) for positron emission tomography (PET) scans combined with either computed tomography (CT) or magnetic resonance imaging (MRI) is increasing for prostate cancer diagnosis. There is a need for direct comparison of the two tests to demonstrate the benefit of 68Ga-PSMA PET/MRI for determining tumor stage in prostate cancer.Take home messageAfter the recent US Food and Drug Administration approval of 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA) positron emission tomography (PET) for staging of primary prostate cancer (PCa), it is expected that the use of this imaging modality will increase rapidly. Our review of the literature shows that 68Ga-PSMA PET/magnetic resonance imaging has high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/computed tomography in primary PCa staging. There is an urgent need for direct head-to-head comparison of the two diagnostic tests in future research.

Dataset Information

Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [⁶⁸Ga]Ga-TC3-OGDOTA.

Publications

Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [<sup>68</sup>Ga]Ga-TC3-OGDOTA.

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