Details zur Publikation

Referenztyp Zeitschriften
DOI / URL Link
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.;
Journal / Serie Molecules
Erscheinungsjahr 2020
Department OEC;
Band/Volume 25
Heft 10
Sprache englisch;
POF III (gesamt) T42;
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.
ID 23273
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