% IMPORTANT: The following is UTF-8 encoded. This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.
@INPROCEEDINGS{Humpert:1026498,
author = {Humpert, Swen and Elsner, Anna-Lena and Zlatopolskiy, Boris
and Neumaier, Bernd},
title = {{T}owards covalent fibroplast activation protein ({FAP})
inhibitors for delivery of therapeutic radionuclides into
{FAP}-positive tumors},
reportid = {FZJ-2024-03442},
year = {2023},
abstract = {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.},
month = {May},
date = {2023-05-22},
organization = {25th International Symposium on
Radiopharmaceutical Sciences, Honolulu
(USA), 22 May 2023 - 26 May 2023},
subtyp = {After Call},
cin = {INM-5},
cid = {I:(DE-Juel1)INM-5-20090406},
pnm = {5253 - Neuroimaging (POF4-525)},
pid = {G:(DE-HGF)POF4-5253},
typ = {PUB:(DE-HGF)6},
url = {https://juser.fz-juelich.de/record/1026498},
}