Radiosynthesis and initial in vitro evaluations of [¹⁸F]KBM-1 as a potential RAR-α imaging agent

Objectives Retinoic acid receptor (RAR-α) plays an important role in amyloid plaque formation in Alzheimer's Disease(AD) patients. It has been shown in some animal models that AD can be induced via retinoic acid dysregulation, which is manifested by RAR-α down-regulation. We therefore radiolabeled a novel boron-containing derivative of the RAR-α specific agonist that has been confirmed to bind RAR-α with high affinity and exhibit less cellular toxicity than known RAR agonists, Am580 and ATRA. In this study, we report the radiochemical synthesis of [¹⁸F]KBM-1 for the first time, using ArBF₃^-/KHF₂ chemistry and demonstrate its initial in vitro binding.

Methods The radiochemical synthesis of [¹⁸F]KBM-1 was carried out by formation of [¹⁸F]fluoride pendant arylboronic ester through KHF₂ assisted substitution of [¹⁸F]^- with corresponding p-ArBF₃ at 40 °C for 180 min. In vitro cell uptake assay was performed on human tumor cell line that expresses RARα with and without unlabeled blocking agent to evaluate the specificity and binding efficiency of [¹⁸F]KBM-1. The data was expressed as %ID/mg of protein present in each well with p values ≤ .05 considered statistically significant.

Results [¹⁸F]KBM-1 was synthesized with high radiochemical purity (>98%) and specific activity ~3000 mCi/µmol (decay corrected to EOS). [¹⁸F]KBM-1 was produced in 13% decay corrected radiochemical yield (n>10) in a total synthesis and formulation time of 3.0 h. From the in vitro cell uptake assay results, the uptake of [¹⁸F]KBM-1 was inhibited by blockade ~50%, 34% and 35% after 5, 15 and 60 min of incubation times respectively.

Conclusions [¹⁸F]KBM-1 was synthesized for the first time using the ArBF₃^-/KHF₂ chemistry with high radiochemical purity and specific activity. The in vitro cell uptake assay indicate that [¹⁸F]KBM-1 has the potential to serve as a RAR-α imaging agent with further in vivo studies.