[11C]Methyl-incorporated JQ1; a novel PET probe for in vivo epigenetic imaging

553 Objectives Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) which regulate gene expression by binding to acetylated histones and controlling the assembly of histone acetylation-dependent chromatin complexes, are known to be involved in several diseases such as cancer, inflammation and atherosclerosis. JQ1 is a specific inhibitor of BET proteins which has been developed for cancer therapy and is also used as a chemical probe to investigate the role of BET proteins in carcinogenesis and inflammation. To develop a novel PET probe for in vivo epigenetic imaging targeting BET proteins, we have synthesized a [11C]CH3-incorporated JQ1 derivative ([11C]Me-JQ1). Methods A suitable position for incorporation of [11C]methyl group into JQ1 was determined by computational drug design approaches based on target protein structure and the binding affinity of Me-JQ1 to BET protein was determined by biomolecular interaction. [11C]Me-JQ1 was synthesized by Pd(0)-mediated rapid C-[11C]methylation (quality of [11C]Me-JQ1: specific radioactivity of 74 GBq/µmol, chemical and radiochemical purities of both >99%). In vitro and in vivo uptake of [11C]Me-JQ1 into cancer cells were then evaluated by using A549 (human adenocarcinoma) and C6 (rat glioma) cells, which highly express BRD2 and BRD4. Results The Kd value of Me-JQ1 was approximately 70 nM. In vitro experiment showed that [11C]Me-JQ1 was incorporated both into A549 and C6 cells, which were blocked by applications of unlabeled JQ1 and Me-JQ1. PET imaging and radiometabolite analysis also showed the uptake of [11C]Me-JQ1 into A549 and C6 xenograft tumors. Conclusions The epigenetic imaging by PET will be helpful for personalized cancer medicine and drug developments.