Druglike, 18 F-labeled PET Tracers Targeting Fibroblast Activation Protein

Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-call...

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Published in:Journal of medicinal chemistry 2024-05, Vol.67 (9), p.7068-7087
Main Authors: Tanc, Muhammet, Filippi, Nicolò, Van Rymenant, Yentl, Grintsevich, Sergei, Pintelon, Isabel, Verschuuren, Marlies, De Loose, Joni, Verhulst, Emile, Moon, Euy Sung, Cianni, Lorenzo, Stroobants, Sigrid, Augustyns, Koen, Roesch, Frank, De Meester, Ingrid, Elvas, Filipe, Van der Veken, Pieter
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Endopeptidases - metabolism
Female
Fluorine Radioisotopes - chemistry
Gelatinases - antagonists & inhibitors
Gelatinases - metabolism
Humans
Membrane Proteins - antagonists & inhibitors
Membrane Proteins - metabolism
Mice
Positron-Emission Tomography - methods
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - pharmacokinetics
Radiopharmaceuticals - pharmacology
Serine Endopeptidases - metabolism
Tissue Distribution
Citations: Items that this one cites
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Summary:Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives. FAPIs typically have a relatively high molecular weight and contain very polar, multicharged chelator moieties. While this is not limiting the application of FAPIs in oncology, more druglike FAPIs could be required to optimally study diseases characterized by denser, less permeable tissue. In response, we designed the first druglike F-labeled FAPIs. We report target potencies, biodistribution, and pharmacokinetics and demonstrate FAP-dependent uptake in murine tumor xenografts. Finally, this paper puts forward compound as a highly promising, druglike FAPI for F-PET imaging. This molecule is fit for additional studies in fibrosis and its preclinical profile warrants clinical investigation.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c02402