Synthesis and characterization of 4,6‐dichloroindole‐based radioligands for imaging the glycine site of the NMDA ion channel

Abstract To provide effective PET or SPECT ligands for the glycine binding site of the NMDA ion channel, we have synthesized and characterized in vitro four substituted derivatives of the potent glycine site antagonist 3‐[2‐[(phenylamino)carbonyl]ethenyl]‐4,6‐dichloroindole‐2‐carboxylic acid (Ki=3.0 nM). These new ligands contain groups amenable to labeling with C‐11 for PET, or I‐123 for SPECT. In vitro analysis of these compounds revealed that placement of a methoxy group at either the ortho or para position of the phenylaminocarbonyl group significantly reduced receptor affinity (Ki=74.0±8.1 and 26.5±4.9 nM, respectively), as did placement of an iodine at the para position (Ki=60.4±8.2 nM). However, the meta‐methoxy derivative (4b) maintained high affinity (Ki=4.8±0.9 nM) for the glycine site and was therefore labeled with carbon‐11 by reacting the corresponding desmethyl derivative with [11C]methyl iodide. Radiochemical yields of 14±10% (EOS), and high specific activity (1.2±0.5 Ci/μmol (EOS, n=7)) were realized, and the product was prepared in a sterile saline solution suitable for in vivo use. Copyright © 2002 John Wiley & Sons, Ltd.