Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP)

Decker, An De; Vliegen, Gwendolyn; Rompaey, Dries Van; Peeraer, Anke; Bracke, An; Verckist, Line; Jansen, Koen; Geiss‐Friedlander, Ruth; Augustyns, Koen; Winter, Hans De; Meester, Ingrid De; Lambeir, Anne‐Marie; Veken, Pieter Van der

doi:10.1021/acsmedchemlett.9b00191

Cited by 35 publications

(43 citation statements)

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“…In the inhibition assays, DOTA.SA.FAPi and DATA 5m .SA.FAPi, along with their nonradioactive, metal complexed analogues were characterized for inhibitory potency towards FAP and PREP. Earlier work had shown that the lack of a basic amine function in UAMC1110-based molecules, precludes DPP-affinity in this series (De Decker et al 2019;Jansen et al 2014a). Nonetheless, the FAP/PREP selectivity was shown to be a particularly important parameter to check.…”

Section: Synthesis Of Cold Complexes and Enzyme Inhibition Assaysmentioning

confidence: 85%

“…UAMC1110 is currently still under evaluation as a potential therapeutic in diseases characterized by FAP expression. At the same time, the molecule is being used as a FAP-targeting moiety in so-called activity-based probes that can be used to visualize and quantify FAP activity in tissues and organisms (De Decker et al 2019 ). Highly relevant examples have also been published that rely on radionuclide-based reporter systems, such as XY-FAP-02 developed by Yang et al (Yang et al 2019 ) .…”

Section: Introductionmentioning

confidence: 99%

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Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

EJNMMI radiopharm. chem.

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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 chelatorlinker systems. Here, we report squaric acid (SA) containing bifunctional DATA 5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA 5m .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-ofconcept in vivo animal study followed by ex vivo biodistribution were determined with [ 68 Ga]Ga-DOTA.SA.FAPi. Results: [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DATA 5m .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 DATA 5m .SA.FAPi and its nat Ga and nat Lu-labeled derivatives were excellent resulting in low nanomolar IC 50 values of 0.7-1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC 50 with 1.7-8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [ 68 Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUV mean 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.

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Section: Synthesis Of Cold Complexes and Enzyme Inhibition Assaysmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

EJNMMI radiopharm. chem.

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“…Earlier work had shown that the lack of a basic amine function in UAMC1110-based molecules, precludes DPP-a nity in this series. [21,22] Nonetheless, the FAP/PREP selectivity was shown to be a particularly important parameter to check. Obtained results are summarized in Table 1.…”

Section: Synthesis Of Dotasafapimentioning

confidence: 99%

“…At the same time, the molecule is being used as a FAP-targeting moiety in so-called activitybased probes that can be used to visualize and quantify FAP activity in tissues and organisms. [22] Highly relevant examples have also been published that rely on radionuclide-based reporter systems, such as XY-FAP-02 developed by Yang et al [23] They used a DOTAGA chelator combined with an alkyl chain as linker system bound to the FAP-inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Targeting fibroblast activation protein (FAP): Next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

Preprint

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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 containing bifunctional DATA5m and DOTA chelators relied on UAMC1110. Results The radiopharmaceuticals DOTA.SA.FAPi and DATA5m.SA.FAPi were synthesized, labeled with gallium-68 and further characterized for in vitro stability, inhibitory efficiency, in vivo targeting properties and ex vivo biodistribution. [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation after already 10 minutes and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and its natGa and natLu-labeled derivatives were in low nanomolar range. Comparable results were obtained for DATA5m.SA.FAPi and its natGa analogue. Additionally, all five compounds showed low affinity for the related protease PREP (high µM range). 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 and low background signal. Ex vivo biodistribution showed high tumor uptake at 60 min post injection with overall low uptake in healthy tissues. Conclusion In this work, novel PET radiotracers targeting fibroblast activation protein (FAP) 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.

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“…I realized that maybe these high-throughput methods may work in some cases but not for all targets. Then I realized that specific FAP inhibitors had been described by Jansen et al (8)(9)(10), and our chemists modified these molecules and immediately had success. So you need a little luck.…”

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confidence: 99%

A Conversation Between Uwe Haberkorn and Johannes Czernin

Haberkorn

Czernin

2019

J Nucl Med

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and head of the Clinical Cooperation Unit in Nuclear Medicine at the German Cancer Research Center (Deutsche Krebsforschungszentrum [DKFZ]; both in Heidelberg, Germany). After moving from ultrasound and CT to nuclear medicine, he soon established a molecular biology laboratory and concentrated first in tumor metabolism related to the expression of the relevant genes, then moved to apoptosis imaging and the use of benzamides for diagnosis and therapy of melanomas, both together with his colleague Michael Eisenhut. Fascinated by the use of viral vectors for the transfer of suicide genes into tumors, he worked on the construction of adenoassociated vectors bearing tissue-specific promoters and then on the development of virla vectors transferring antiangiogenetic genes in tumors. Finally, he concentrated on the use of high-throughput methods such as phage and ribosome display for the identification of peptides binding to target proteins overexpressed in tumors. He has been awarded the Mallinckrodt Prize of the German Society for Nuclear Medicine (1996), the First Prize for Contrast Research from the German Röntgen Society (1998), and the Erwin Schrödinger Prize of the Helmholtz Association of German Research Institutes (2018). Dr. Czernin: Your educational path was somewhat unusual-you started out studying philosophy for 2 y. Dr. Haberkorn: I didn't study philosophy alone. I also studied German literature. My initial intention was to study classic German philosophers, but I ended up studying contemporary American philosophers like Hilary Putnam, Willard van Orman Quine, and Wilfrid Sellars, and, up to the present day, people like Daniel Dennett and Thomas Nagel. My first intention was to become a philosopher. Dr. Czernin: And did you graduate with a degree in philosophy? Dr. Haberkorn: I had a midterm examination in German literature about the History of Agathon from Christoph Martin Wieland after 1 y. This was quite fast-half the time one usually needs. I also had a midterm essay ready to submit for philosophy about Gottlob Frege's theory of meaning. It was then that I realized that medicine might be a better job for bread and butter. Dr. Czernin: It's kind of a survival choice. Dr. Haberkorn: Maybe, but I realized that when you engage in medical research you may be as creative as a philosopher. Before I

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Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP)

Cited by 35 publications

References 28 publications

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Targeting fibroblast activation protein (FAP): Next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

A Conversation Between Uwe Haberkorn and Johannes Czernin

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