Comparison of high and low molar activity TSPO tracer [<sup>18</sup>F]F-DPA in a mouse model of Alzheimer’s disease

Keller, Thomas H.; López-Picón, Francisco R.; Krzyczmonik, Anna; Forsbäck, Sarita; Takkinen, Jatta; Rajander, Johan; Teperi, Simo; Dollé, Frédéric; Rinne, Juha O.; Haaparanta‐Solin, Merja; Solin, Olof

doi:10.1177/0271678x19853117

Cited by 19 publications

(21 citation statements)

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“…The molar activity is an important parameter that should be considered with radiopharmaceuticals that target receptors or proteins since there is only a limited number of proteins available in the targeted tissue. Decreasing the molar activity can result in a saturation of the target protein, rendering a lower activity uptake in the targeted tissue [22]. This effect is not observed in the case of necrosis-avid cyanines.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

et al. 2020

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Purpose Current clinical measurements for tumor treatment efficiency rely often on changes in tumor volume measured as shrinkage by CT or MRI, which become apparent after multiple lines of treatment and pose a physical and psychological burden on the patient. Detection of therapy-induced cell death in the tumor can be a fast measure for treatment efficiency. However, there are no reliable clinical tools for detection of tumor necrosis. Previously, we studied the necrosis avidity of cyanine-based fluorescent dyes, which suffered long circulation times before tumor necrosis could be imaged due to low hydrophilicity. We now present the application of radiolabeled 800CW, a commercially available cyanine with high hydrophilicity, to image tumor necrosis in a mouse model. Procedures We conjugated 800CW to DOTA via a PEG linker, for labeling with single-photon emission-computed tomography isotope indium-111, yielding [111In]In-DOTA-PEG4-800CW. We then investigated specific [111In]In-DOTA-PEG4-800CW uptake by dead cells in vitro, using both fluorescence and radioactivity as detection modalities. Finally, we investigated [111In]In-DOTA-PEG4-800CW uptake into necrotic tumor regions of a 4T1 breast tumor model in mice. Results We successfully prepared a precursor and developed a reliable procedure for labeling 800CW with indium-111. We detected specific [111In]In-DOTA-PEG4-800CW uptake by dead cells, using both fluorescence and radioactivity. Albeit with a tumor uptake of only 0.37%ID/g at 6 h post injection, we were able to image tumor necrosis with a tumor to background ratio of 7:4. Fluorescence and radioactivity in cryosections from the dissected tumors were colocalized with tumor necrosis, confirmed by TUNEL staining. Conclusions [111In]In-DOTA-PEG4-800CW can be used to image tumor necrosis in vitro and in vivo. Further research will elucidate the application of [111In]In-DOTA-PEG4-800CW or other radiolabeled hydrophilic cyanines for the detection of necrosis caused by chemotherapy or other anti-cancer therapies. This can provide valuable prognostic information in treatment of solid tumors.

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Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

et al. 2020

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“…The synthesis of [ 18 F]F-DPA was synthesized as described previously 46 . Rats were anesthetized with 1.5-2.5% isoflurane/oxygen on the heating bed for micro PET/CT (Inveon multimodality PET/CT, Siemens Medical Solutions, fuji Knoxville, TN, USA) and a few drops of Oftagel (25 mg/g; Santen, Tampere, Finland) were applied to prevent eye dryness.…”

Section: Methodsmentioning

confidence: 99%

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist

et al. 2021

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Rationale: Olfactory ensheathing cell (OEC) transplantation has emerged as a promising therapy for spinal cord injury (SCI) repair. In the present study, we explored the possible mechanisms of OECs transplantation underlying neuroinflammation modulation. Methods: Spinal cord inflammation after intravenous OEC transplantation was detected in vivo and ex vivo by translocator protein PET tracer [ 18 F]F-DPA. To track transplanted cells, OECs were transduced with enhanced green fluorescent protein (eGFP) and HSV1-39tk using lentiviral vector and were monitored by fluorescence imaging and [ 18 F]FHBG study. Protein microarray analysis and ELISA studies were employed to analyze differential proteins in the injured spinal cord after OEC transplantation. The anti-inflammation function of the upregulated protein was also proved by in vitro gene knocking down experiments and OECs/microglia co-culture experiment. Results: The inflammation in the spinal cord was decreased after OEC intravenous transplantation. The HSV1-39tk-eGFP-transduced OECs showed no accumulation in major organs and were found at the injury site. After OEC transplantation, in the spinal cord tissues, the interleukin-1 receptor antagonist (IL-1Ra) was highly upregulated while many chemokines, including pro-inflammatory chemokines IL-1α, IL-1β were downregulated. In vitro studies confirmed that lipopolysaccharide (LPS) stimulus triggered OECs to secrete IL-1Ra. OECs significantly suppressed LPS-stimulated microglial activity, whereas IL-1Ra gene knockdown significantly reduced their ability to modulate microglial activity. Conclusion: The OECs that reached the lesion site were activated by the release of pro-inflammatory cytokines from activated microglia in the lesion site and secreted IL-1Ra to reduce neuroinflammation. Intravenous transplantation of OECs has high therapeutic effectiveness for the treatment of SCI via the secretion of IL-1Ra to reduce neuroinflammation.

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“…[ 18 F]F-DPA was synthesized via two different approaches resulting in different A m s. High A m (360-900 GBq/μmol at EOS) [ 18 F]F-DPA was produced by a copper-mediated nucleophilic 18 F-fluorination methodology [26]. The electrophilic syntheses of [ 18 F]F-DPA, resulting in lower A m (10 GBq/ μmol at EOS), were performed according to previously described procedures [24].…”

Section: Methodsmentioning

confidence: 99%

Evaluation of [18F]F-DPA as a target for TSPO in head and neck cancer under normal conditions and after radiotherapy

Tuominen

Keller

Petruk

et al. 2020

Eur J Nucl Med Mol Imaging

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Background Many malignant tumours have increased TSPO expression, which has been related to a poor prognosis. TSPO-PET tracers have not comprehensively been evaluated in peripherally located tumours. This study aimed to evaluate whether N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([18F]F-DPA) can reflect radiotherapy (RT)-induced changes in TSPO activity in head and neck squamous cell carcinoma (HNSCC). Methods RT was used to induce inflammatory responses in HNSCC xenografts and cells. [18F]F-DPA uptake was measured in vivo in non-irradiated and irradiated tumours, followed by ex vivo biodistribution, autoradiography, and radiometabolite analysis. In vitro studies were performed in parental and TSPO-silenced (TSPO siRNA) cells. TSPO protein and mRNA expression, as well as tumour-associated macrophages (TAMs), were also assessed. Results In vivo imaging and ex vivo measurement revealed significantly higher [18F]F-DPA uptake in irradiated, compared to non-irradiated tumours. In vitro labelling studies with cells confirmed this finding, whereas no effect of RT on [18F]F-DPA uptake was detected in TSPO siRNA cells. Radiometabolite analysis showed that the amount of unchanged [18F]F-DPA in tumours was 95%, also after irradiation. PK11195 pre-treatment reduced the tumour-to-blood ratio of [18F]F-DPA by 73% in xenografts and by 88% in cells. TSPO protein and mRNA levels increased after RT, but were highly variable. The proportion of M1/M2 TAMs decreased after RT, whereas the proportion of monocytes and migratory monocytes/macrophages increased. Conclusions [18F]F-DPA can detect changes in TSPO expression levels after RT in HNSCC, which does not seem to reflect inflammation. Further studies are however needed to clarify the physiological mechanisms regulated by TSPO after RT.

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Comparison of high and low molar activity TSPO tracer [¹⁸F]F-DPA in a mouse model of Alzheimer’s disease

Cited by 19 publications

References 28 publications

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist

Evaluation of [18F]F-DPA as a target for TSPO in head and neck cancer under normal conditions and after radiotherapy

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Comparison of high and low molar activity TSPO tracer [18F]F-DPA in a mouse model of Alzheimer’s disease

Cited by 19 publications

References 28 publications

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist

Evaluation of [18F]F-DPA as a target for TSPO in head and neck cancer under normal conditions and after radiotherapy

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Comparison of high and low molar activity TSPO tracer [¹⁸F]F-DPA in a mouse model of Alzheimer’s disease