Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography

Abstract

MS-275 (Entinostat) is a histone deacetylase (HDAC) inhibitor currently in clinical trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood brain barrier (BBB) and cause region specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomography (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we determined that [(11)C]MS-275 has low uptake in brain tissue when administered intravenously to non-human primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [(11)C]MS-275 were not changed by the co-administration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compounds for peripheral cancer treatment (where CNS exclusion is often advantageous), but also for the treatment of neurological disorders (where CNS penetration is critical).

Figure 1

Structures of SAHA and MS-275.

Figure 2

Synthesis of the labeling precursor and [¹¹C]MS-275. Reagents and conditions: (i) CDI, THF, reflux, 3 h, 50%; (ii) TFA, CHCl₃, rt, 2 h, 96% then HCl, Et₂O; (iii) ¹¹CO₂, DBU, DMF, 75 °C, 7 min, 25% RCY.

Figure 3

[¹¹C]MS-275 PET Imaging (baboon brain): (a) summed PET images (2−90 min) following injection of [¹¹C]MS-275 (4.85 mCi); (b) PET image superimposed with a structural MRI of the brain from the same baboon.

Figure 4

Time−activity curves derived from PET imaging data for peripheral organs in the baboon torso following administration of [¹¹C]MS-275 (4.74 mCi).

Figure 5

Baboon plasma analysis: (●) percentage (of total radioactivity) of [¹¹C]MS-275 in plasma over time; (○) metabolite-corrected plasma integral.

Figure 6

Rodent imaging experiments with [¹¹C]MS-275. (a) Summed PET images (1−90 min) following injection of [¹¹C]MS-275: (top) baseline scan (1.74 mCi); (bottom) image acquired following pretreatment with MS-275 (40 mg/kg ip; 1.39 mCi). Images are dose corrected. (b) Whole-brain time−activity curves generated from imaging data.

Figure 7

Ratio of radioactivity in brain and blood (at 2 h) for mice coadministered [¹¹C]MS-275 with nonradioactive MS-275 at two doses: ∗ indicates injection of [¹¹C]MS-275 only.