Synthesis and Evaluation of ¹⁸F-INER-1577-3 as a Central Nervous System (CNS) Histone Deacetylase Imaging Agent

Epigenetic dysfunction is implicated in many neurologic, psychiatric and oncologic diseases. Consequently, histone deacetylases (HDACs) inhibitors have been developed as therapeutic and imaging agents for these diseases. However, only a few radiotracers have been developed as HDACs imaging agents for the central nervous system (CNS). We report herein the synthesis and evaluation of [¹⁸F]INER-1577-3 ([¹⁸F]5) as an HDACs imaging agent for CNS.

[¹⁸F]INER-1577-3 ([¹⁸F]5) was synthesized by two methods: one-step (A) and two-step (B) methods. Briefly, radiofluorination of the corresponding precursors (11, 12) with K[¹⁸F]/K2.2.2 followed by purifications with HPLC gave ([¹⁸F]5). The quality of [¹⁸F]INER- 1577-3 synthesized by these methods was verified by HPLC and TLC as compared to an authentic sample. The inhibitions of [¹⁸F]INER-1577-3 and related HDACs inhibitors on tumor cells growth were carried out with breast cancer cell line 4T1 and MCF-7. The whole-body and brain uptake of [¹⁸F]INER-1577-3 in rats and AD mice were determined using a micro-PET scanner and the data was analyzed using PMOD.

The radiochemical yield of [¹⁸F]INER-1577-3 synthesized by these two methods was 1.4 % (Method A) and 8.8% (Method B) (EOB), respectively. The synthesis time was 115 min and 100 min, respectively, from EOB. The inhibition studies showed that INER-1577-3 has a significant inhibitory effect in HDAC6 and HDAC8 but not HDAC2. PET studies in rats and AD mice showed a maximum at about 15 min postinjection for the whole brain of a rat (0.47 ± 0.03 %ID/g), SAMP8 mice (5.63 ± 1.09 %ID/g) and SAMR1 mice (7.23 ± 1.21 %ID/g).

This study showed that INER-1577-3 can inhibit tumor cell growth and is one of a few HDACs inhibitors that can penetrate the blood-brain barrier (BBB) and monitor HDAC activities in AD mice. Thus, [¹⁸F]INER-1577-3 may be a potent HDACs imaging agent, especially for CNS.