Synthesis, in vitro and in vivo evaluation of [¹¹C]‐methyl‐BIII277CL as a pet radioligand for imaging the pcp‐binding site of the NMDA‐receptor complex

Abstract

The N-methyl-D-aspartate (NMDA), a subtype of glutamate receptors, is a ligandgated ion channel, which contributes to excitatory neurotransmission throughout the central nervous system (CNS). It plays a crucial role in brain development, synaptic plasticity and the pathophysiology of major neurological disorders, such as stroke, traumatic brain injury, epilepsy, Parkinson's and Huntington's disease (1). A large number of NMDA antagonists have thus 'been labelled with either "C or I8F as potential agents for imaging the PCP (phencyclidine)-binding site of the NMDA receptor complex. However, to date none of these radioligands has proved to be useful. As part of our programme on the development of radioligands for the glutamatergic NMDA-receptor complex, we have synthesized and evaluated the potential of Methyl-BIII277CL (2, Fig. 1) as an imaging agent for the PCP-binding site of the NMDA-receptor complex: The corresponding desmethyl compound, BIII277CL a, Fig.1) has previously been described and is a potent NMDA antagonist with high. selectivity for the PCP binding site (2-4). Figure 1: Synthesis of Methyl-BlII277CL (2). Methyl-BlII277CL(2) was prepared by reacting the desmethyl compound I with dimethylsulfate. The chemical yield of 2 was greater 90%. In vitro receptor screening assays were carried out on more than 20 CNS receptors. Whereas 2 at a concentration of 0.1pM failed to alter the binding of radioligands to almost all the examined CNS receptors, substantial inhibitory effects (80% inhibition) were observed at the PCP-binding site. To further characterize its in v i m binding affinity