Design, synthesis, biochemical evaluation, radiolabeling and in vivo imaging with high affinity class-IIa histone deacetylase inhibitor for molecular imaging and targeted therapy

High-Contrast PET imaging with [18F]-NT160, a Class-IIa Histone Deacetylase (Class-IIa HDAC) Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System

“…The radiosynthesis of [ 18 F]-NT160 was performed similar to our previous report 28, 29 with modifications. Performing the radiochemical reaction at 175 o C with the addition of a small quantity (0.3-0.5 mg) of 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (known as 4-hydroxy-TEMPO or TEMPOL) led to a significant improvement of the radiochemical yield of 7.5 ±1.0%, (decay corrected) and the molar activity of 0.55–0.96 GBq/umol (15–26 mCi/umol) compared to the previous work: radiochemical yield of 2-5% (decay corrected) and the molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol) 28 .…”

“…The use of 4-hydroxy-TEMPO allowed for performing the reaction at 165 °C, a relatively higher temperature than 150 o C used in our previous report 28, 29 . Interestingly, increasing the radiochemical reaction to 175-200 o C produced similar radiochemical yields but with significantly reduced molar activity.…”

“…We surmised that M1 arises from the cleavage of the amide bond thus producing 4-(5-[ 18 F]-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid ([ 18 F]- 1 ) (Figure 7A). We then investigated whether the nonradioactive 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid ( 1 ) can inhibit HDACs using the cell-based assay similar to our previous report 28 . Our data demonstrate that the IC50 of compound 1 is >10.0 uM (Figure 6 B-C and Figure S.I) for all HDAC classes and thus compound 1 is not an effective inhibitor of HDACs.…”

“…Our data demonstrate that the IC50 of compound 1 is >10.0 uM (Figure 6 B-C and Figure S.I) for all HDAC classes and thus compound 1 is not an effective inhibitor of HDACs. Compound 1 exhibited poor inhibition (~10%) of class-I, class-IIb and IIa HDACs activities (Figure 7B-C) when compared side-by-side with SAHA (panHDAC inhibitor with higher selectivity to class-I and class-IIb HDACs 39 ) and the parent NT160 (selective class-IIa HDAC) 28 . The weak affinity of compound 1 to class-I and class-IIb HDACs is highly desirable, since off target binding to these proteins that are expressed in the brain 40, 41 may complicate the PET data quantification.…”

The Novel Class IIa Selective Histone Deacetylase Inhibitor YAK540 Is Synergistic with Bortezomib in Leukemia Cell Lines

“…We intended to improve the physicochemical properties and potency of TMP269 and thus developed YAK540 as a new selective class IIa HDACI. In the meantime, further improved class IIa selective HDACIs were developed such as NT160 [ 18 ] and compound 12 [ 19 ]. Yet, in this study we compare the first well-established trifluoromethyloxadiazolyl (TFMO)-type class IIa selective inhibitor TMP269 with our novel inhibitor YAK540.…”