| Autor: |
Sadeghzadeh, M., Wenzel, B., Gündel, D., Deuther-Conrad, W., Toussaint, M., Moldovan, R.-P., Fischer, S., Teodoro, R., Jonnalagadda, S., Jonnalagadda, S. K., Mereddy, V. R., Drewes, L. R., Brust, P. |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Molecules 25(2020)10, 2309 |
| Popis: |
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 PET radiotracer for imaging of MCTs, which encouraged us to develop the novel analogs 1 and 2 of FACH. They were synthesized via Buchwald-Hartwig amination starting from m-anisidine followed by Vilsmeier-Haack formylation and Knoevenagel condensation in moderate overall yields. MCT1 inhibition was estimated by [14C]lactate uptake assay on rat brain endothelial (RBE4) cells. Although 2 showed 25-times lower MCT1 inhibitory potency than FACH (IC50 = 11 nM), compound 1 could be a suitable PET candidate with an IC50 value of 118 nM. Therefore, 1 was selected for radiosynthesis of [18F]1 and subsequent biological evaluation as a potential PET radiotracer for imaging of the MCT expression in mouse brain. By in vitro autoradiography in cryosections of the mouse kidney, 50% displacement of [18F]1 by 10 µM of the specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid (α-CHC) was observed. Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, in vivo brain uptake of [18F]1 was in a similar range, likely to be related to similar transport rates by MCTs on RBE4 cells. The high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by α-CHC, suggests the suitability of [18F]1 for imaging of the MCTs expression in vivo. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
