Direct electrophilic fluorination of tyrosine in dermorphin analogues and its effect on biological activity, receptor affinity and selectivity

In a preliminary communication we reported [(Tetrahedron Lett. 31, 619 (1990)] that acetyl hypofluorite can be used efficiently to introduce fluorine regiospecifically (ortho to OH) into the phenolic ring of tyrosine‐containing peptides. This procedure has been applied to the fluorination of a number of μ‐selective opioid peptides derived from dermorphin. While the procedure can be used even when the side chains of Arg, Lys, and Tyr are left unprotected, the sulfoxide of a Met(O)‐containing analogue was oxidized to sulfone faster than fluorination of the phenolic ring. This method can also be used when the peptide is attached to Merrifield resin. Thus, Tyr(3‐F)‐d‐Ala‐Phe‐Gly‐NH2 and Tyr(3‐F)‐d‐Arg‐Phe‐Lys‐NH2 (F‐DALDA) have been prepared, purified, and characterized. Affinities of these fluorinated peptides for both μ‐and δ‐opioid receptors are reduced (two‐ to nine‐fold) relative to their nonfluorinated analogues, but their selectivity for μ‐opioid receptors is not significantly altered. Similarly, the in vitro biological potencies (GPI and MVD assays) of the fluorinated analogues are reduced (two‐ to seven‐fold) relative to their nonfluorinated parent peptides. Thus, F‐DALDA, which has high affinity (K δ= 15.2nM) and selectivity (K δ/K δ= 5390) for μ‐opioid receptors, has potential use in biochemical studies which utilize 19F or 18F‐ labeled compounds.