Hauptseite > Publikationsdatenbank > Towards covalent fibroplast activation protein (FAP) inhibitors for delivery of therapeutic radionuclides into FAP-positive tumors > print

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100 1 _ |a Humpert, Swen
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111 2 _ |a 25th International Symposium on Radiopharmaceutical Sciences
|g ISRS2023
|c Honolulu
|d 2023-05-22 - 2023-05-26
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245 _ _ |a Towards covalent fibroplast activation protein (FAP) inhibitors for delivery of therapeutic radionuclides into FAP-positive tumors
260 _ _ |c 2023
336 7 _ |a Conference Paper
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520 _ _ |a Objectives: Fibroblast activation protein (FAP) inhibitors based on a(4-quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold are promising leadstructures for the development of FAP-selective positron emissiontomography (PET) tracers.1 However, due to their fastwashout, they arenot suitable for delivery of therapeutic radionuclides into FAP-positivetumor lesions. The aim of the present work was to overcome thislimitation by replacement of the cyano group with a sulfonyl fluoridebasedwarhead, which should enable irreversible covalent binding ofthe inhibitor through an in vivo click reaction with the active-siteserine residue.2 Radiofluorination of the warhead was used as astrategy to verify formation of covalent binding by detection of thedeliberated [18F]fluoride.Methods: First the FAP inhibitor scaffold was prepared by a threestepconvergent synthesis. The sulfonyl fluoridewarheadwas preparedby a five step convergent synthesis starting from N-Cbz-L-prolinol. Thismoiety was acylated with 4-quinoloyl-glycine conventionally accessiblein three steps. Radiolabeling was performed using a protocol forultrafast 18F/19F isotopic exchange by “SuFEx click chemistry”.3 To thisend, [18F]fluoride was loaded onto a QMA anion exchange cartridgeand eluted with a solution of BnEt3NCl in MeOH. Followingevaporation of the solvent and addition of the radiolabeling precursorin MeCN (1 mL), the reaction was allowed to proceed at 0°C for 5 minunder argon without stirring. Isolation of the radiotracer for subsequentstability tests in various media at different pH values wasperformed by solid phase extraction (SPE) on a C-18 cartridge.Results: The radiolabeling precursorwas obtained in a total yield of11% over nine steps and radiolabeled with radiochemical conversionsof 50 ± 11% (n = 7), affording the desired radiofluorinated compound inactivity yields of 27 ± 1.4% (n = 4) after isolation by SPE. Subsequentincubation studies demonstrated excellent stability of the radiolabeledproduct in acidic media at pH values between 4 and 5 for at least twohours, even after heating at 100 °C for 5 min. However, the compoundexhibited defluorination in H2O, phosphate-buffered saline (PBS) atphysiological pH (7.4), and rapid defluorination in blood serum, with ahalf-life of 117,124 and 5.7 min, respectively. Due to lowstability of thetracer in PBS and blood serum, further optimization of the structure iscurrently ongoing before binding studies will be performed by in vivoPET imaging.Conclusions: A modified FAP inhibitor derivative with a sulfonylfluoride-based warhead was successfully synthesized and radiofluorinated.However, in vivo covalent binding of the warhead to theFAP enzyme could not be examined due to insufficient stability inblood serum and at physiological pH value.References1. Jansen K., Heirbaut L., Cheng J. D., Joossens J., Ryabtsova O., Cos P.,Maes L., Lambeir A-M., De Meester I., Augustyns K., Van derVeken P., ACS Med. Chem. Lett. 2013, 4, 491–496.2. Narayanan A., Jones L. H., Chem. Sci. 2015, 6, 2650–2659.3. Walter N., Bertram J., Drewes B., Bahutski V., Timmer M., SchützM. B., Krämer F., Neumaier F., Endepols H., Neumaier B.,Zlatopolskiy B. D., Eur. J. Med. Chem. 2022, 237, 114383.
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700 1 _ |a Zlatopolskiy, Boris
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700 1 _ |a Neumaier, Bernd
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