Details zur Publikation

Kategorie Textpublikation
Referenztyp Zeitschriften
DOI 10.3390/molecules25102309
Lizenz creative commons licence
Titel (primär) Development of novel analogs of the monocarboxylate transporter ligand FACH and biological validation of one potential radiotracer for positron emission tomography (PET) imaging
Autor Sadeghzadeh, M.; Wenzel, B.; Gündel, D.; Deuther-Conrad, W.; Toussaint, M.; Moldovan, R.-P.; Fischer, S.; Ludwig, F.-A.; Teodoro, R.; Jonnalagadda, S.; Jonnalagadda, S.K.; Schüürmann, G.; Mereddy, V.R.; Drewes, L.R.; Brust, P.
Quelle Molecules
Erscheinungsjahr 2020
Department OEC
Band/Volume 25
Heft 10
Seite von art. 2309
Sprache englisch
Supplements https://www.mdpi.com/1420-3049/25/10/2309/s1
Keywords monocarboxylate transporters (MCTs); FACH; 18F-labeled analog of FACH; α-CCA; blood-brain barrier (BBB); positron emission tomography (PET) imaging
Abstract Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [18F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [18F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [14C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [18F]1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D7.4 result for [18F]1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, the in vivo brain uptake of [18F]1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.
dauerhafte UFZ-Verlinkung https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=23273
Sadeghzadeh, M., Wenzel, B., Gündel, D., Deuther-Conrad, W., Toussaint, M., Moldovan, R.-P., Fischer, S., Ludwig, F.-A., Teodoro, R., Jonnalagadda, S., Jonnalagadda, S.K., Schüürmann, G., Mereddy, V.R., Drewes, L.R., Brust, P. (2020):
Development of novel analogs of the monocarboxylate transporter ligand FACH and biological validation of one potential radiotracer for positron emission tomography (PET) imaging
Molecules 25 (10), art. 2309 10.3390/molecules25102309