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

• Published in: Bioorganic & medicinal chemistry letters 2017-03, Vol.27 (6), p.1425-1427
• Main Authors: Solingapuram Sai, Kiran Kumar, Das, Bhaskar C., Sattiraju, Anirudh, Almaguel, Frankis G., Craft, Suzanne, Mintz, Akiva
• Format: Article
• Language: English
• Subjects: All-trans retinoic acid (ATRA); Animals; Benzopyrans - chemistry; Benzopyrans - pharmacokinetics; Benzopyrans - pharmacology; Biodistribution; Boron Compounds - chemistry; Boron Compounds - pharmacokinetics; Boron Compounds - pharmacology; Cell Line, Tumor; Drug Screening Assays, Antitumor; Fluorine Radioisotopes - metabolism; Heterografts; Humans; Kidney - metabolism; Liver - metabolism; Mice; Mice, Inbred BALB C; Neuroblastoma; Neuroblastoma - metabolism; Retinoic acid receptor alpha (RAR-α); Retinoic Acid Receptor alpha - agonists; Retinoic Acid Receptor alpha - metabolism; Tissue Distribution
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.01.093

Ratio of target (tumor): nontarget (muscle) at 5min, 30min and 60min post injection of [18F]KBM-1 in mice bearing neuroblastoma tumor (n=4). [Display omitted] Retinoic acid receptor alpha (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-α, and expression of RAR-α is upregulated after treatment. A molecular imaging probe that binds RAR-α 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 [18F]KBM-1, a novel RAR-α agonist. The radiochemical synthesis of [18F]KBM-1 was carried out through KHF2 assisted substitution of [18F]− from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [18F]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 5min to 60min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30min to 60min post injection. Tumor uptake in subset of 30min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [18F]KBM-1 as a RAR-α imaging agent.