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.
Bibliographical noteFunding Information:
Funding: Masoud Sadeghzadeh was kindly financially supported by the Alexander von Humboldt Foundation and L. R. Drewes was supported by the University of Minnesota Foundation. This research received no further external funding.
Acknowledgments: The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to K. Franke and A. Mansel for providing [18F]fluoride as well as Matthias Scheunemann and Susann Schröder for their scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR-MS spectra.
© 2020 by the authors.
- Blood-brain barrier (BBB)
- F-labeled analog of FACH
- Monocarboxylate transporters (MCTs)
- Positron emission tomography (PET) imaging