Nuklearmedizin 2020; 59(02): 95
DOI: 10.1055/s-0040-1708137
Leuchttürme
Leuchtturm-Sitzung 6: Molekulares Targeting
© Georg Thieme Verlag KG Stuttgart · New York

Development of FAP-inhibitors based on squaric acid linked DOTA and DATA5m chelators

ES Moon
1   Johannes Gutenberg-University, Institute of Nuclear Chemistry, Mainz,, Germany
,
F Elvas
2   Antwerp University Hospital, Department of Nuclear Medicine, Antwerp,, Belgium
,
G Vliegen
3   University of Antwerp, Department of Pharmaceutical Sciences, Antwerp,, Belgium
,
E Eppard
4   PositronPharma SA, Santiago de Chile,, Chile
,
L Greifenstein
1   Johannes Gutenberg-University, Institute of Nuclear Chemistry, Mainz,, Germany
,
A Jallapally
3   University of Antwerp, Department of Pharmaceutical Sciences, Antwerp,, Belgium
,
B Klasen
1   Johannes Gutenberg-University, Institute of Nuclear Chemistry, Mainz,, Germany
,
V Kramer
4   PositronPharma SA, Santiago de Chile,, Chile
,
Meester I De
3   University of Antwerp, Department of Pharmaceutical Sciences, Antwerp,, Belgium
,
S Staelens
2   Antwerp University Hospital, Department of Nuclear Medicine, Antwerp,, Belgium
,
P Van der Veken
3   University of Antwerp, Department of Pharmaceutical Sciences, Antwerp,, Belgium
,
F Rösch
1   Johannes Gutenberg-University, Institute of Nuclear Chemistry, Mainz,, Germany
› Institutsangaben
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Publikationsverlauf

Publikationsdatum:
08. April 2020 (online)

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Ziel/Aim Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and involved in tumour–promoting processes. FAP represents an attractive target for diagnostic and therapeutic applications. In this work, new chelator-conjugates using squaric acid as linker unit based on a 4,4-difluoro substituted 2-cyanopyrrolidine FAP-inhibitor1 (UAMC1110) were synthesized and evaluated.

Methodik/Methods The two precursors DOTA.SA.FAPi and DATA5m.SA.FAPi were synthesized, purified by HPLC, radiolabeled and evaluated. For these compounds and the cold complexes of both derivatives with natGa and natLu, in vitro binding affinities to FAP and to PREP were measured and the selectivity index to FAP was determined. First in vivo PET studies were generated in HT-29 human xenograft mouse model.

Ergebnisse/Results [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation >98 % RCY after 15 min and high stabilities over a period of 2 h > 95 % intact conjugates in HS, PBS, saline and EtOH. The affinities to FAP of DOTA.SA.FAPi, DATA5m.SA.FAPi, natGa/natLu-metalled DOTA.SA.FAPi and natGa-complexed DATA5m.SA.FAPi were excellent with very low nanomolar IC50-values (range of 0.7-1.4 nM). Additionally, all five compounds showed a low affinity for PREP (high µM-IC50 values) resulting in high selectivity to FAP with a high selectivity index FAP/PREP of >2000 up to 6700. First in vivo animal PET-imaging studies were performed (n = 3) and biodistribution studies showed high tumor uptake of mean 5.2 ± 0.2 % ID/g at 60 min p.i. with overall low uptake in healthy tissues.

Schlussfolgerungen/Conclusions Novel FAPI-compounds DOTA.SA.FAPi and DATA5m.SA.FAPi were successfully evaluated with regard to radiolabeling, in vitro stability with Gallium-68 and in vitro binding assay. First proof-of-principle in vivo studies in HT-29 xenograft mice showed promising results with high accumulation in tumor and low background signal at 60 min p.i. Further detailed animal imaging studies and patient studies are currently in progress.

 

  • Literatur/References

  • 1 Jansen K. et al., J Med Chem. 57 ( (07) ), 3053-3074 2014; .
    PubMed