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

A new class of delta opioid antagonists was recently discovered in which th e sequence Tyr-Tic was used as a message domain. The substitution of Tyr(1) by Dmt enhanced the delta selectivity and antagonist activity. The excelle nt properties of these ligands stimulated us to prepare the corresponding t ritiated derivatives. Peptides containing Tic at position 2 undergo spontan eous diketopiperazine formation in some solvents, with a reduction in opioi d activity. To avoid this side-reaction we synthesised the N,N-dimethylated analogue (N,N(Me)(2)-Dmt-Tic-OH), which was found to be stable. On the bas is of this result, we prepared diiodinated analogues of H-Dmt-Tic-OH and N, N(Me)(2)-Dmt-Tic-OH to undergo catalytic dehalotritiation. Products of high specific radioactivity were obtained: 44.67 Ci/mmol for [H-3]Dmt-Tic-OH an d 59.88 Ci/mmol for [H-3]N,N(Me)(2)-Dmt-Tic-OH.