Fluorinated analogues of a wide range of structurally different classes of organic compounds ,have been prepared and many of these have proven to be important pharmacological and medicinal agents. The advantages of fluorine substitution in large part arise from the small van der Waals radius of fluorine (1.35 Angstrum). As a result, fluorine bonded to an sp(2)-carbon is used effectively as a C-H replacement. Furthermore, because of similar aliphatic C-F and C-O bond lengths (1.39 Angstrum and 1.43 Angstrum, respectively) and because of the weak hydrogen bond- accepting ,property of the former, fluorine bonded to an sp'-carbon has been used frequently as an OH surrogate, particularly in carbohydrate research. Thus, because of steric and some electronic similarities, fluorinated compounds often mimic their nonfluorinated parents with respect to recognition by biological macromoleculer systems such as enzymes, transport proteins and receptors. On the other hand, the high electronegativity of fluorine (4.0) can drastically alter electron density distribution in the molecule which, in turn, affects pK(a)'s of neighboring functional groups and molecular dipole moments. All these altered physics-chemical properties of the molecule, as a result of fluorine substitution, can result in drastically modified biological properties such as potency 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 of fluorinated molecules as biological markers. """"""""F Although many methods have been developed for fast and efficient incorporation of """"""""F and into various compounds of medicinal importance, such methods in general have not been practical for direct incorporation into peptides. We have now developed a method for fast, efficient introduction of F regiospecifically into the phenolic ring of Tyr-containing peptides by use of electrophilic fluorinating agent acetyl hypofluorite (AcOF). We have used this method for fluorinating ii-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 develop a very micro-selective (Ki(delta)/Ki(delta) =5390) fluoro peptide [Tyr(3-F)-D-Arg-Phe-Lys-NH(2)] which may be used as an useful research tool to probe the complex opioid receptor system.
