6533b822fe1ef96bd127cb1a

RESEARCH PRODUCT

Synthesis, labelling and evaluation of hydantoin-substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N-methyl-d-aspartate receptor

subject

description

The N-methyl- d-aspartate (NMDA) receptor as a type of ionotropic glutamatergic receptors is essential for physiological processes such as learning, memory and synaptic plasticity. A glutamate-induced overactivation of these receptors, accompanied by increased intracellular calcium concentration, causes cell injury and leads to a large number of acute or chronic neurological disorders, such as stroke, trauma, Parkinson's disease and Alzheimer's disease. In an attempt to visualise the glutamatergic neurotransmission in vivo with positron emission tomography, novel fluoroethoxy- and methoxy-substituted reference compounds based on the lead structure of a hydantoin-substituted indole-2-carboxylic acid were synthesised. The affinities towards the glycine binding site of the NMDA receptor showed Ki values between 322 and 11 nM and the lipophilicities ranged from logD values of 1.51 to 2.53. On the basis of these results, precursor compounds were synthesised containing a phenolic hydroxy moiety to obtain the radiolabelled ligands through an alkylation reaction. Radiosynthesis was achieved by labelling the precursor ethyl 4,6-dichloro-3-((3-(4-hydroxyphenyl)-2,4-dioxoimidazolidin-1-yl)methyl)-indole-2-carboxylate with 2-[18F]fluoroethyl tosylate or [11C]methyl iodide and subsequent cleavage of the ethyl ester moiety. This gave the final products in overall decay-corrected radiochemical yields of 5–7% and 6–9% and specific activities of 24–67 GBq/µmol and 8–26 GBq/µmol, respectively.