Abstract
1103
Objectives: Microtubule loss from axons and dendrites is a key contributor to nervous system degeneration during Alzheimer’s disease, Parkinson disease and other neurodegenerative diseases. Non-invasive quantification of microtubule expression using PET can impact the choice of therapy as well as monitor the progress of treatment. We developed radiochemical synthesis and evaluated two blood brain barrier (BBB) penetrating microtubule PET radiotracers, [11C]MPC6827 and [11C]HD800 in rodent brain for the first time. In this study, we report PET imaging studies using [11C]MPC6827 and [11C]HD800 in non-human primate (NHP) brain.
Methods: The radiochemical synthesis of [11C]MPC6827 and [11C]HD800 were automated on a GE-FX2MeI/FX2M radiochemistry module by alkylating the corresponding desmethyl precursor with [11C]MeI in DMF using NaOH. To demonstrate translational utility of the synthesized radiotracers, dynamic 0-120 min PET imaging studies were conducted using [11C]MPC6827 and [11C]HD800 in adult male rhesus monkeys (n=2). Time Activity Curves (TACs) were generated as the mean PET values in whole brain.
Results: [11C]MPC6827 and [11C]HD800 were synthesized with high radiochemical purity (>98%) and high specific activity (~2600 mCi/µmol, n >10) with 40% radiochemical yield, decay corrected to EOS. PET imaging analyses indicated brain penetration and retention of both the radiotracers in monkey brain. Time activity curves (TACs) indicated relatively moderate binding of [11C]MPC6827 and [11C]HD800 when compared to the TACs generated in mice. Both the radiotracers exhibited identical regional distribution, especially around the cerbellum regions in monkey brain.
Conclusions: PET imaging studies in monkey brains show that [11C]MPC6827 and [11C]HD800 penetrates the BBB with moderate uptake across the brain regions. Binding distribution of the radiotracer is in good agreement with the known distribution of microtubule tracers in mouse brain. Further experiments to determine radiometabolites and quantification of microtubule binding of [11C]MPC6827 and [11C]HD800 in NHP brain are in progress.