Development of Novel Analogs of the Monocarboxylate Transporter Ligand FACH and Biological Validation of One Potential Radiotracer for Positron Emission Tomography (PET) Imaging
Masoud Sadeghzadeh,
Barbara Wenzel,
Daniel Gündel,
Winnie Deuther-Conrad,
Magali Toussaint,
Rareş-Petru Moldovan,
Steffen Fischer,
Friedrich-Alexander Ludwig,
Rodrigo Teodoro,
Shirisha Jonnalagadda,
Sravan K. Jonnalagadda,
Gerrit Schüürmann,
Venkatram R. Mereddy,
Lester R. Drewes,
Peter Brust
Affiliations
Masoud Sadeghzadeh
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Barbara Wenzel
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Daniel Gündel
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Winnie Deuther-Conrad
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Magali Toussaint
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Rareş-Petru Moldovan
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Steffen Fischer
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Friedrich-Alexander Ludwig
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Rodrigo Teodoro
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
Shirisha Jonnalagadda
Department of Chemistry and Biochemistry, Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA
Sravan K. Jonnalagadda
Department of Chemistry and Biochemistry, Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA
Gerrit Schüürmann
UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany
Venkatram R. Mereddy
Department of Chemistry and Biochemistry, Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA
Lester R. Drewes
Department of Biomedical Sciences, University of Minnesota Medical School Duluth, 251 SMed, 1035 University Drive, Duluth, MN 55812, USA
Peter Brust
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany
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.
