Toward the Characterisation of the Pharmacological Action of a Series of AMPAR Modulators using a PET Probe

Ionotropic glutamate receptors (iGluRs) play a key role in the majority of fast central nervous system excitatorysynaptic transmission, and are divided into three sub-groups: NMDA, AMPA and kainate receptors.(1) AMPA receptors (AMPARs) have been extensively investigated and are recognised for their involvement in long-term potentiation (LTP), linked to the processes of learning and memory. As such, AMPAR represents a valid cognitive enhancer target, particularly in the fight against Alzheimer’s disease. (2,3) Benzothiadiazine 1,1-dioxides have emerged as important allosteric modulators of AMPARs, based upon the discovery of cyclothiazide AMPAR activity in 1993 (Fig. 1).(4) Recently, BPAM121 was synthesised in the group, with improved activity and metabolic stability compared to precursor BPAM97 (Fig. 1).(5) This work documents an investigation into the pharmacological action of this class of compounds through the synthesis and initial optimisation of (18F)-labelled BPAM121, to be used as a PET probe in vivo. Biological evaluation of this compound in vivo will follow.
References
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2) J. Keifer, Z. Zheng, Eur. J. Neurosci., 2010, 32, 269-277.
3) L. Gao et al., J. Neurochem., 2016, 136, 620-636.
4) K. A. Yamada, C.-M. Tang, J. Neurosci., 1993, 13, 3904-3915.