Abstract
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Objectives: Microtubules (MTs) are highly abundant in the body and are one of the major components of cytoskeleton structure. The misalignment of MTs contributes to the pathogenesis of many neurodegenerative disorders, and malignancies, and is involved in brain injuries. [11C]MPC-6827 and [11C]HD-800 developed by our team are the only PET radiotracers currently available for MT target that penetrates blood brain barrier (BBB) and exhibit specific binding in brain.1,2 Herein, we present the radiosynthesis and evaluation of promising MT ligands labeled with 18F, a more translational PET radioisotope and demonstrate retained target binding in vitro an ability to cross the BBB with PET imaging.
Methods: Synthesis of [18F]FEMPC-6827 and [18F]FEHD-800 were achieved by reacting corresponding desmethyl precursors with [18F]FEOTs or direct radiofluorionation of corresponding tosylate with [18F]fluoride. In vitro tubulin binding of FEMPC-6827 and FEHD-800 were performed by displacement of [11C]MPC-6827 uptake in MBA-MD-231 cells. Competitive binding of FEMPC-6827 and FEHD-800 to brain targets were performed through NIMH-PDSP. Dynamic microPET image acquisition were performed in anesthetized male white mice with Trifoil mPET/CT for 60 minutes.
Results: Synthesis of [18F]FEMPC-6827 and [18F]FEHD-800 were achieved in 40+5% in >99% radiochemical purity with a molar activity of 74+18.5 GBq/μmol. FEMPC-6827 and FE-HD-800 did not exhibit competitive binding to a number of brain targets. microPET study in mice show that [18F]FEMPC-6827 and [18F]FE-HD-800 penetrates the BBB and retained in brain. Both tracers did not show radio[18F]fluorination in vivo and binding are similar to the parent ligands [11C]MPC-6827 and [11C]HD-800.
Conclusions: Our studies show that fluoroethyl analogues of MPC-6827 and HD-800 show similar binding to corresponding methyl analogues with MTs as evident from radioligand displacement assays and microPET in mice. Research Support: Diane Goldberg Foundation (NYSPI/CUMC); NCATS UL1TR001873 (Reilly) Irving Institute/CTSA Translational Therapeutics, Accelerator; CTSA WFSM TIP (UL1TR001420). References: 1. Kumar JSD et al. Radiosynthesis and In vivo evaluation of [11C]MPC-6827, the first brain penetrant microtubule PET ligand, J. Med. Chem. 2018, 61(5), 2118 2. Solingapuram Sai K K et al., Radiosynthesis and evaluation of [11C]HD-800, a high affinity brain penetrant PET tracer for imaging microtubules, ACS Medicinal Chemistry Letters, 2018, 9 (5), 452-456.