Radiolabeling and initial biological evaluation of [F-18]KBM-1 for imaging RAR-alpha receptors in neuroblastoma

摘要

Retinoic acid receptor alpha (RAR-alpha) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated 13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-alpha, and expression of RAR-alpha, is upregulated after treatment. A molecular imaging probe that binds RAR-alpha will help clinicians to diagnose and stratify risk for patients with neuroblastoma, who could benefit from retinoid-based therapy. In this study, we report the radiolabeling, and initial in vivo evaluation of [(18)F1KBM-1, a novel RAR-alpha, agonist. The radiochemical synthesis of [F-18]KBM-1 was carried out through KHF2 assisted substitution of [F-18](-) from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [F-18]KBM-1 was significantly inhibited by all three blocking agents (KBM-1, ATRA, BD4) at all the selected incubation times. Standard biodistribution in mice bearing neuroblastoma tumors demonstrated increased tumor uptake from 5 min to 60 min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30 min to 60 min post injection. Tumor uptake in subset of 30 min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [F-18]KBM-1 as a RAR-alpha imaging agent. (C) 2017 Elsevier Ltd. All rights reserved.