Detection of BET protein-expressing cancer cells by PET with [11C]Me-JQ1

1180 Objectives Hyperacetylated chromatin is involved in various diseases and is regulated by the bromodomain and extra-terminal (BET) proteins which recognize the acetylated histones and regulate gene expression. JQ1, a specific inhibitor of BET proteins binding to acetylated histones, has been tried for clinical application as an anti-cancer drug. To develop the PET probes for detection of hyperacetylated chromatin and BET protein-expressing cancers, we have synthesized 11C-labeled methyl-JQ1 ([11C]Me-JQ1). Methods To evaluate the characteristic of Me-JQ1, we examined the binding affinity and anti-cancer effect. The synthesis of [11C]Me-JQ1 was carried out by rapid C-[11C]-methylation. Incorporation of [11C]Me-JQ1 and expression levels of BET proteins (BRD2 and BRD4) were evaluated with human lung carcinoma and glioma cells in vitro and in vivo. Results Me-JQ1 showed a similar BET protein-binding affinity and anti-cancer effects to JQ1. The specific incorporation of [11C]Me-JQ1, which was blocked by pretreatment of unlabeled (+)JQ1 but not by (-)JQ1, was closely correlated to the expression levels of BET proteins in cancers. In addition, the anti-cancer JQ1 sensitivity of cancers was also dependent on the BET protein expression levels. PET imaging with xenograft models showed that accumulation of [11C]Me-JQ1 in tumor was high in JQ1-sensitive- but low in JQ1 less-sensitive cancer. Conclusions Specific cellular incorporation of [11C]Me-JQ1 is closely correlated to the expression levels of BET proteins in cancers. [11C]Me-JQ1 can identify the JQ1-sensitive BET protein-expressing cancers, and thus may be useful for personalized cancer medicine.