Synthesis of 5‐[ 125 I]‐iodo‐zacopride, a new probe for 5‐HT 3 receptor binding sites

In an attempt to develop a specific probe of serotonin 5‐HT 3 receptors, various methods have been investigated to synthesize a radioiodinated derivative of the potent 5‐HT 3 antagonist zacopride. The direct iodination of 5‐dechloro‐zacopride 2 was performed using NaI in the presence of either chloramine T or iodo‐beads. Irreproducible results or/and low yields were obtained by these methods. A third approach using a less oxidative medium allowed the synthesis of iodo‐zacopride 4 from 2 with N‐iodo‐succinimide or with NaI and N‐chlorosuccinimide. Using this third condition, high yield was obtained (49%). However, the radioiodinated compound was contaminated by some “cold” zacopride also formed during the reaction. A two step synthesis was successful to eliminate “cold” zacopride but in lower yield (2‐10%). Thus, 4‐amino‐2‐methoxy‐benzoate 5 was iodinated and then coupled with 3‐aminoquinuclidine 8 to give 5‐iodo‐zacopride 4 . Radioactive synthesis was carried out in the same condition to give 5‐[ 125 1]‐iodo‐zacopride 1 with a yield of 98%. The two enantiomers R‐and S‐5‐[ 125 1]‐iodo‐zacopride were synthesized by direct iodination.