Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Introduction
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. Recently, we reported on [18F]FACH as a novel MCT-targeting imaging agent (1), whose limited blood-brain barrier permeability, however, excludes application in brain diseases. Accordingly, we aimed to develop a more lipophilic FACH-derived radiotracer possessing higher brain uptake.
Materials and Methods
Two 2-fluoropyridinyl-substituted analogs of FACH (1 and 2) were obtained by Buchwald-Hartwig cross coupling reaction.
The potency of 1 and 2 to inhibit MCT1 was measured by [14C]lactate uptake assay using rat brain endothelial-4 cells. Radiolabeling of [18F]1 was proceeded using 1 mg nitro precursor and [18F]fluoride in the presence of Kryptofix and K2CO3 in dimethyl sulfoxide at 130 °C within 15 min. The logD7.4 value of [18F]1 was experimentally determined in the n-octanol-PBS system. For biological evaluation of [18F]1, in vitro autoradiography on cryosections of mouse kidney and small animal PET-MRI studies in female CD-1 mice were performed. Target specificity was proven by using the sodium salt of the MCT inhibitor α-cyano-4-hydroxycinnamic acid (α-CCA-Na).

Results
The analogs 1 and 2 inhibited MCT1 with IC50 values of 118 and 274 nM, respectively. [18F]1 was obtained by radiofluorination of the nitro precursor via nucleophilic aromatic substitution reaction with radiochemical yields of 73 ± 12% (n = 4, non-isolated, radio-HPLC), a high radiochemical purity of ˃ 98% and molar activities in the range of 180-200 GBq/µmol (n = 3, end of synthesis) using starting activities of 2-3 GBq. The logD7.4 value of 0.82 achieved for [18F]1 indicated 2-fold higher lipophilicity in comparison to [18F]FACH (2). 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 α-CCA-Na (10 µM). The brain uptake of [18F]1 was similar to [18F]FACH without significant washout and an almost unchanged SUV of 0.15 between 15 and 60 min p.i.
Conclusion
Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, the brain uptake of [18F]1 was in a similar low range, revealing the need for further structural modification. However, a high and specific uptake of the new radiotracer in the kidneys suggests suitability of [18F]1 for investigations on the expression of MCT in vivo.
References
(1) Sadeghzadeh M, et al. J Label Compd Radiopharm.2019; 62: 411-424.
(2) Sadeghzadeh M, et al. Sci Rep. 2019; 9: 18890-18897.