Title:Synthesis and Evaluation of <sup>18</sup>F-INER-1577-3 as a Central Nervous System (CNS) Histone Deacetylase Imaging Agent
VOLUME: 16 ISSUE: 8
Author(s):Ming-Hsin Li *, Han-Chih Chang , Chun-Fang Feng, Hung-Wen Yu and Chyng-Yann Shiue
Affiliation:Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Department of Nuclear Medicine, National Taiwan University Hospital Taipei
Keywords:Epigenetic modifications, histone deacetylases, [18F]INER-1577-3, histone deacetylases imaging agents, PET imaging,
AD mice.
Abstract:
Background: 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.
Methods: [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.
Results: 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).
Conclusion: 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.
