The purinergic P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). This ionotropic receptor family contains seven subunits P2X1-7. P2X receptors are involved in various physiological processes and associated with a variety of diseases including cancer, cardiovascular and neurological diseases. P2X4 is a predominant subtype highly expressed in various central nervous system (CNS) areas, on immune cells and peripheral macrophages. The over expression of P2X4 is linked to neuroinflammation, which is an essential step in the progression of brain diseases. P2X4 has become a novel molecular target for treatment and PET (positron emission tomography) imaging of neuroinflammation and associated brain diseases such as Alzheimer’s disease. 5-BDBD (5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1, 4]diazepin-2-one) is a specific P2X4 antagonist. We are interested in the development of PET P2X4 radioligands. In our previous work, we have developed carbon-11-labeled 5-BDBD derivatives as new potential PET probes for imaging of P2X4 receptor. In this ongoing study, we report the synthesis of a fluorine-18-labeled 5-BDBD derivative 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD) as a new potential PET radioligand for P2X4 receptor. The reference standard 5-(3-(2-fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (FE-5-BDBD) and its corresponding tosylated precursor 2-(3-(2-oxo-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepin-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (TsOE-5-BDBD) were synthesized from commercially available starting materials 2-hydroxybenzonitrile with 2-bromo-1-(3-methoxyphenyl)ethan-1-one in 5 steps with 22%, and 5 steps with 34% overall chemical yield, respectively. The target tracer [18F]FE-5-BDBD was prepared by nucleophilic substitution of the tosylated precursor TsOE-5-BDBD with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) in a home-built automated multi-purpose 18F-radiosynthesis module. The decay corrected radiochemical yield from K[18F]F of [18F]FE-5-BDBD was 15-25%, and specific activity at end of bombardment (EOB) was 111-740 GBq/mmol.

Synthesis of 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one as a new potential PET radioligand for P2X4 receptor

254th National Meeting (2017)

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