The Synthesis and Evaluation of [18F]BPAM121: Potential of an AMPA Receptor Positive Allosteric Modulator

AMPA receptors (AMPARs), one of three sub-groups of ionotropic glutamate receptors present in the central nervous system, are recognised for their involvement in long-term potentiation (LTP), and learning and memory processes.1 They represent a valid cognitive enhancer target, particularly in the fight against Alzheimer’s disease (AD).2,3 Benzothiadiazine 1,1-dioxides, such as BPAM121, have emerged as important allosteric modulators of AMPARs, working solely in the presence of the endogenous transmitter.4 Synthesis of BPAM121 labelled with fluorine-18 was proposed, to investigate the utility of this molecule as a PET probe in vivo, and evaluate its potential as an AD diagnostic tool (Figure 1).

Figure 1. a) Structure of BPAM121, b) Established radiochemical synthesis of [18F]BPAM121

This work documents the successful optimization of synthesis, purification and formulation of [18F]BPAM121 using an automated FASTlab (GE Healthcare) synthesizer. In particular, the influence of higher-level [18F]fluoride ion starting concentrations on final product formulation requirements is discussed. Finally, results from biological studies of [18F]BPAM121, confirmed to successfully pass the blood brain barrier, are discussed.

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[4] P. Francotte et al., J. Med. Chem. 2010, 53, 1700-1711.