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Purpose: The anorectic effect of PYY3–36 makes it a potential pharmacological weight loss treatment. Modifications of the endogenous peptide to obtain commercially attractive pharmacological and biophysical stability properties are examined. Methods: Half-life extended PYY3–36 analogues were prepared and examined regarding Y2-receptor potency as well as biophysical and stability properties. Results: Deamidation of asparagine in position 18 and 29 was observed upon incubation at 37°C. Asparagine in position 18 – but not position 29 – could be substituted to glutamine without detrimental effects on Y2-receptor potency. Covalent dimers were formed via the phenol impurity benzoquinone reacting with two N-terminal residues (Isoleucine-Lysine). Both residues had to be modified to suppress dimerization, which could be done without negatively affecting Y2-receptor potency or other stability/biophysical properties. Introduction of half-life extending modifications in position 30 and 35 eliminated aggregation at 37°C without negatively affecting other stability properties. Placement of a protracting moiety (fatty acid) in the receptor-binding C-terminal region reduced Y2-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY3–36 analogues formed oligomers of various sizes depending on primary structure and solution conditions. Conclusions: By rational design, a chemically and physically stable Y2-receptor selective, half-life extended PYY3–36 peptide has been developed. [ABSTRACT FROM AUTHOR]