Fluorinated analogues of many bioorganic compounds have become important pharmacological and medicinal agents. The advantages of fluorine substitution arise from its small van der Waals radius (1.35 A). As a result, florine bonded to a trigonal carbon is used effectively as a C-H replacement. Because of similar aliphatic C-F and C-O bond lengths (1.39 and 1.43 A, respectively), the halogen bonded to a tetrahedral carbon has been used frequently as an OH surrogate, particularly in studies with nucleoside analogues. These steric similarities allow fluorinated compounds to mimic their nonfluorinated parents with respect to recognition by various biological macromolecules such as enzymes, transport proteins and receptors. On the other hand, the high electonegativity of fluorine (4.0) can drastically alter electron density distribution in the molecule which, in turn, affects pK values in neighboring groups and molecular dipole moments. All these altered physicochemical properties, as a result of fluorine substitution, can result in drastically modified biological properties such as potency, transport and receptor selectivity. Furthermore, recent advances in 19-F NMR and electron energy-loss spectroscopic techniques, and 18-F positron-emission tomography (18-F PET), have increased the significance and application of fluorinated molecules as biological markers and diagnostic agents. Although many methods have been developed for rapid and efficient incorporation of 18-F and 19-F into various molecules, such methods have not been generally practical for peptides. We have now developed a method for fast, efficient introduction of fluorine regiospecifically into the phenolic ring of tyrosine-containing peptides by use of the electrophilic fluorinating mu-selective opioid peptides. In vitro bioassays and receptor-binding assays have revealed that these fluoro peptides retain their high receptor selectivity. Thus, we have been able to prepare a very mu- selective fluoropeptide [Tyr(3-F)-D-Arg-Phe-Lys-NH2], which is already in use as a research tool to probe the complex opioid receptor system.
