Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2 ', 6 ' dimethyltyrosine

Recently a new class of ~ opioid antagonists has been discovered by using Tyr-Tic sequence. The substitution of Tyr 1 by Dmt resulted in a new analogue (H-Dmt-Tic-OH) with enhanced affinity and selectivity. Because of its excellent property we chose it for labelling with tritium. At the same time peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, and they lose some of their binding ability. To avoid this unwanted side- reaction we synthetized the N-methylated analogue (N,N(Me)2- Dmt-Tic-OH), and it was more stable under storage condition, but 5 affinity declined moderately. On the basis of this information we prepared diiodinated analogues of these dipeptides. Catalytic dehalotritiation of precursors resulted in tritiated peptides. High specific radioactivity, 44.67 Ci/mmol with [3H]Dmt-Tic-OH and 59.88 Ci/mmol with N,N(Me)2-[ 3H]Dmt-Tic-OH were achieved.