In vivo imaging and characterization of [18F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET

Vicidomini, Caterina; Panico, Mariarosaria; Greco, Adelaide; Gargiulo, Sara; Coda, Anna Rita Daniela; Zannetti, Antonella; Gramanzini, Matteo; Roviello, Giovanni N.; Quarantelli, Mario; Alfano, Bruno; Tavitian, Bertrand; Dollé, Frédéric; Salvatore, Marco; Brunetti, Arturo; Pappatà, Sabina

doi:10.1016/j.nucmedbio.2014.11.009

Cited by 57 publications

(25 citation statements)

References 57 publications

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“…Nonspecific and physiological distribution of the 18 F-DPA-714 was clearly visualized in the heart, lung, liver, kidney, gallbladder, small intestine and bladder as reported previously [16, 17], with a mean uptake ratio of 1.08±0.04 in the heart (Fig 2A and 2B). Scaffold-free iPSC-cardiac sheet that was generated from the cell-clusters, of which 90% were troponin T-positive cardiomyocytes, was transplanted over the dorsal side of the subcutaneous space to determine the SUVmax of the iPSC-cardiac sheet.…”

Section: Resultssupporting

confidence: 84%

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Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

et al. 2016

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Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of the allogeneic iPSC-cardiac. This imaging tool may enable the understanding and monitoring host-immune response of the host, allogeneic cell transplantation therapy.

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Section: Resultssupporting

confidence: 84%

“…The PET scan was acquired for 10 minutes. This duration for static PET imaging was selected based on the previous study when the whole body distribution became stabilized [16]. The PET images were reconstructed using OSEM3D-MAP (Matrix size; 256*256) by a software module of the scanner.…”

Section: Methodsmentioning

confidence: 99%

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

et al. 2016

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“…TSPO has been investigated as biomarker for inflammatory conditions of lung, liver, kidney, and brain, etc. Its role has also been studied in other disorders such as depression, anxiety, and neurodegenerative disorders (Hatori et al, 2014;Jean et al, 2015;Jones, Marino, Shakur, & Morrell, 2003;Kraus, Kadriu, Lanzenberger, Zarate, & Kasper, 2019;Lagarde, Sarazin, & Bottlaender, 2018;Veenman & Gavish, 2006;Vicidomini et al, 2015). Therefore, high affinity TSPO ligands can find application for noninvasive diagnosis of pathologically affected tissues.…”

Section: Introductionmentioning

confidence: 99%

Modified benzoxazolone (ABO‐AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein

Srivastava

Kakkar

Kumar

et al. 2019

Drug Development Research

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Acetamidobenzoxazolone (ABO) has been modified to ABO‐AA, 2‐(2‐(5‐bromo/chloro benzoxazolone)acetamide)‐3‐(1H‐indol‐3‐yl)propionate to improve pharmacokinetics and lipophilicity (log p = 2.04). The final compound was synthesized in better yield and in fewer steps than previously reported MBIP‐Br (70% vs. 62%). Computational docking confirmed binding of MBIP‐Cl with translocator protein (TSPO) as well as with mutant TSPO (−8.99 for PDB: 4RYQ and −9.30 for PDB: 4UC1, respectively). Ex‐vivo biodistribution and scintigraphy showed that 99mTc‐MBIP‐Cl is better than 99mTc‐MBIP‐Br in terms of uptake in TSPO‐rich organs and release kinetics 0–120 min postinjection. At 15 min, uptake was 2.75‐fold (12.91%ID/g vs. 4.69%ID/g) in lung and seven‐fold (5.16%ID/g vs. 0.72%ID/g) in heart for 99mTc‐MBIP‐Cl compared to that of 99mTc‐MBIP‐Br which gives warrant to utilize this single photon emission computed tomography agent in higher animals.

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“…; Vicidomini et al . ), their use in PET imaging of neuroinflammation remains challenging. TSPO radioligands exhibit a high non‐specific binding, have complex kinetics and variable concentrations in plasma‐free fractions across human clinical cohorts (Chauveau et al .…”

mentioning

confidence: 99%

“…Historically, nearly all neuroinflammation PET radiotracer research was related with the 18-kDa translocator protein (TSPO, formerly called peripheral benzodiazepine receptor). Despite the great efforts that have been made in the development of TSPO radioligands (Boutin et al 2007;Endres et al 2009;Van Camp et al 2010;Damont et al 2015;Vicidomini et al 2015), their use in PET imaging of neuroinflammation remains challenging. TSPO radioligands exhibit a high non-specific binding, have complex kinetics and variable concentrations in plasma-free fractions across human clinical cohorts (Chauveau et al 2008;Owen and Matthews 2011;Turkheimer et al 2015).…”

mentioning

confidence: 99%

Discovery of a fluorinated 4‐oxo‐quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2

Slavik

Herde

Haider

et al. 2016

Journal of Neurochemistry

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The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [(18) F]RS-126 was obtained in ≥ 99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [(18) F]RS-126 showed a logD7.4 value of 1.99 and is stable in vitro in rat and human plasma over 120 min, whereas 55% intact parent compound was found in vivo in rat blood plasma at 10 min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in in vivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [(18) F]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [(18) F]RS-126 using PET imaging. In summary, [(18) F]RS-126 demonstrated high specificity toward CB2 receptor in vitro and in vivo and is a promising radioligand for imaging CB2 receptor expression. Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [(18) F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in in vivo displacement experiments with rats. Time activity curve of [(18) F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).

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In vivo imaging and characterization of [18F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET

Cited by 57 publications

References 57 publications

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

Modified benzoxazolone (ABO‐AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein

Discovery of a fluorinated 4‐oxo‐quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2

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