TY - JOUR
T1 - Development of novel analogs of the monocarboxylate transporter ligand FACH and biological validation of one potential radiotracer for positron emission tomography (PET) imaging
AU - Sadeghzadeh, Masoud
AU - Wenzel, Barbara
AU - Gündel, Daniel
AU - Deuther-Conrad, Winnie
AU - Toussaint, Magali
AU - Moldovan, Rareş Petru
AU - Fischer, Steffen
AU - Ludwig, Friedrich Alexander
AU - Teodoro, Rodrigo
AU - Jonnalagadda, Shirisha
AU - Jonnalagadda, Sravan K.
AU - Schüürmann, Gerrit
AU - Mereddy, Venkatram R.
AU - Drewes, Lester R.
AU - Brust, Peter
N1 - Publisher Copyright:
© 2020 by the authors.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - Blood-brain barrier (BBB)
KW - F-labeled analog of FACH
KW - FACH
KW - Monocarboxylate transporters (MCTs)
KW - Positron emission tomography (PET) imaging
KW - α-CCA
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UR - http://www.scopus.com/inward/citedby.url?scp=85084911243&partnerID=8YFLogxK
U2 - 10.3390/molecules25102309
DO - 10.3390/molecules25102309
M3 - Article
C2 - 32423056
AN - SCOPUS:85084911243
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 10
M1 - 2309
ER -