Please use this identifier to cite or link to this item:
Authors: Moon, Euy Sung
Elvas, Filipe
Vliegen, Gwendolyn
De Lombaerde, Stef
Vangestel, Christel
De Bruycker, Sven
Bracke, An
Eppard, Elisabeth
Greifenstein, Lukas
Klasen, Benedikt
Kramer, Vasko
Staelens, Steven
De Meester, Ingrid
Van der Veken, Pieter
Rösch, Frank
Title: Targeting fibroblast activation protein (FAP) : next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators
Online publication date: 22-Apr-2022
Language: english
Abstract: BACKGROUND Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid (SA) containing bifunctional DATA5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA5m.SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-of-concept in vivo animal study followed by ex vivo biodistribution were determined with [68Ga]Ga-DOTA.SA.FAPi. RESULTS [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation > 97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA5m.SA.FAPi and its natGa and natLu-labeled derivatives were excellent resulting in low nanomolar IC50 values of 0.7–1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC50 with 1.7–8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [68Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUVmean of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues. CONCLUSION In this work, novel PET radiotracers targeting fibroblast activation protein were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA5m bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.
DDC: 540 Chemie
540 Chemistry and allied sciences
610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
Information on rights of use:
Journal: EJNMMI radiopharmacy and chemistry
Pages or article number: 19
Publisher: Springer International Publishing
Publisher place: Cham, Switzerland
Issue date: 2020
ISSN: 2365-421X
Publisher DOI: 10.1186/s41181-020-00102-z
Appears in collections:JGU-Publikationen

Files in This Item:
  File Description SizeFormat
targeting_fibroblast_activati-20220422101605679.pdf1.12 MBAdobe PDFView/Open