Synthesis and evaluation of two 18F-labeled novel acetamidobenzoxazolone radioligands for PET imaging of translocator protein (18 kDa)

Objective: Development of PET radioligand for translocator protein [18 kDa, TSPO] to study its role in activation of glial cells in the injured brain as well as in neurodegenerative diseases is one of the most critical issues of PET imaging. Most of PET radioligands bind TSPO with high affinity in small animals; however, their specific bindings are sometimes reduced in human brain. Moreover, many radioligands exhibited mixed affinity with TSPO in “binder” and “non-binder” human subjects. We have developed 2-[5-(4-[11C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([11C]MPMB) with a benzoxazolone moiety as a new PET radioligand for TSPO.1 In this study we synthesized two 18F-fluoroalkyl analogues, [18F]FEBMP and [18F]FPBMP, and to evaluate potentials for imaging of TSPO expression in brain in vivo.Methods: Unlabeled FEBMP and FPBMP were synthesized in house.2 [18F]FEBMP and [18F]FPBMP were prepared by reacting desmethyl precursor with [18F]FEtBr and [18F]FPrBr, respectively. In vitro binding assay, biodistribution, in vitro autoradiography and PET imaging studies of these radioligands were carried out.Results: [18F]FEBMP and [18F]FPBMP were prepared with radiochemical yields of 20-40% based on [18F]fluoroalkyl agent. They were found to specifically bind TSPO with high affinity (Ki = 6.6 ± 0.7 nM and 16.7 ± 2.5 nM). Biodistribution study indicated high accumulation of radioactivity in the TSPO-rich organs. In vitro autoradiography for ischemic rat brain showed that the ratios of radioactive signals in the ipsilateral side compared with the contralateral side were 3.1 for [18F]FEBMP and 2.1 for [18F]FPBMP. PET imaging of therat brains with [18F]FEBMP revealed increased uptake in the ipsilateral side, showing high binding potential (BPND = 2.72 ± 0.27). In vitro autoradiography with [18F]FEBMP for postmortem human brains demonstrated that TSPO rs6971 polymorphism did not give significant effect on the binding sites. Conclusions: [18F]FEBMP is a promising PET ligand for in vivo visualization of neuroinflammation generally occurred in neurodegenerative disorders.Reference: [1] Tiwari AK, et al (2014) J Neurochem, 129, 712. [2] Tiwari AK, et al (2014) Org Biomol Chem, 12, 9621.21st International Symposium on Radiopharmaceutical Science