18F-labeled tracers targeting fibroblast activation protein
Background: Cancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelatorbased theranostics. Unfortunately, the value of ga...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
21 August 2021
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| In: |
EJNMMI radiopharmacy and chemistry
Year: 2021, Volume: 6, Pages: 1-13 |
| ISSN: | 2365-421X |
| DOI: | 10.1186/s41181-021-00144-x |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s41181-021-00144-x Verlag, kostenfrei, Volltext: https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-021-00144-x 
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| Author Notes: | Thomas Lindner, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Christian Kleist, Susanne Krämer, Walter Mier, Jens Cardinale, Hans-Ulrich Kauczor, Dirk Jäger, Jürgen Debus & Uwe Haberkorn |
| Summary: | Background: Cancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelatorbased theranostics. Unfortunately, the value of gallium-68 labeled tracers is limited by their batch size and the short nuclide half-life. To overcome this drawback, radiolabe‑ling with aluminum fluoride complexes and 6-fluoronicotinamide derivatives of the longer-lived nuclide fluorine-18 was established. The novel compounds were tested for their FAP-specific binding affinity. Uptake and binding competition were studied in vitro using FAP expressing HT-1080 cells. HEK cells transfected with the closely related dipeptidyl peptidase-4 (HEK-CD26) were used as negative control. Small animal positron emission tomography imaging and biodistribution experiments were per‑formed in HT-1080-FAP xenografted nude mice. [18F]AlF-FAPI-74 was selected for PET/ CT imaging in a non-small cell lung cancer (NSCLC) patient. - Results: In vitro, 18F-labeled FAPI-derivatives demonstrated high affinity (EC50 = < 1 nm to 4.2 nm) and binding of up to 80% to the FAP-expressing HT1080 cells while no binding to HEK-CD26 cells was observed. While small animal PET imaging revealed unfavorable biliary excretion of most of the 18F-labeled compounds, the NOTA bearing compounds [18F]AlF-FAPI-74 and -75 achieved good tumor-to-background ratios, as a result of their preferred renal excretion. These two compounds showed the highest tumor accumulation in PET imaging. The organ distribution values of [18F]AlF-FAPI-74 were in accordance with the small animal PET imaging results. Due to its less complex synthesis, fast clearance and low background values, [18F]AlF-FAPI-74 was chosen for clinical imaging. PET/CT of a patient with metastasized non-small cell lung cancer (NSCLC), enabled visualization of the primary tumor and its metastases at the hepatic portal and in several bones. This was accompanied by a rapid clearance from the blood pool and low background in healthy organs. - Conclusion: [18F]AlF-labeled FAPI derivatives represent powerful tracers for PET. Owing to an excellent performance in PET imaging, FAPI-74 can be regarded as a promising precursor for [18F]AlF-based FAP-imaging. |
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| Item Description: | Im Titel ist 18 am Anfang hochgestellt Gesehen am 17.10.2023 |
| Physical Description: | Online Resource |
| ISSN: | 2365-421X |
| DOI: | 10.1186/s41181-021-00144-x |