In vivo uptake of [¹⁸F]KBM-1, a potential PET tracer for neuroblastoma

Objectives Retinoic acid receptor (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high risk neuroblastoma are treated 13-cis-retinoic acid (isotretinoin), which has been shown to reduce the risk of the cancer recurrence. Studies have demonstrated that neuroblastoma cell death is mediated via RAR-α and that expression of RAR-α is upregulated after treatment. Therefore, our objective is to create a molecular imaging probe that binds RAR-α for the purpose of diagnosis and stratification of patients who would benefit from retinoid based therapy. Furthermore, if successful, we would be able to see real-time biologic action of retinoid therapy based on RAR-α upregulation. In this study, we report the initial in vivo evaluation of [¹⁸F]KBM-1, a novel RAR-α agonist.

Methods The radiochemical synthesis of [¹⁸F]KBM-1 was carried out through KHF₂ assisted substitution of [¹⁸F]^- from aryl-substituted pinacolatoesters based retinoid precursor. Biodistribution studies were performed using male BALB/mice with flank neuroblastoma tumors after i.v injection of [¹⁸F]KBM-1. Specific binding was demonstrated by blocking experiment with nonradioactive KBM-1 in the 30 min group.

Results [¹⁸F]KBM-1 was synthesized with high radiochemical purity (>98%) and high specific activity ~3000 mCi/µmol (decay corrected to EOS). Analyzing biodistribution data, from 5 min to 60 min, [¹⁸F]KBM-1 displayed rapid clearance from most of the major organs and bone uptake remained grossly stable, suggesting no significant in vivo metabolic defluorination. The tumor uptake steadily increased from 5 min to 60 min and the uptake ratios for target to non-target (tumor: muscle) increased 1.5 fold to 2.6 fold from 30 min to 60 min p.i. The tumor uptake in the 30 min blocking group was 1.7-fold lower than unblocked.

Conclusions The initial in vivo biodistribution studies in BALB/c tumor bearing mice demonstrate the potential of [¹⁸F]KBM-1 as a radiotracer for imaging neuroblastoma. Further evaluations of the tracer’s in vivo metabolic profile, kinetic studies, quantitative biodistribution/tumor uptake are now being performed.