Identification of a Suitable Peptidic Molecular Platform for the Development of NPY(Y1)R‐Specific Imaging Agents

NPY(Y1)R (neuropeptide Y receptor subtype 1) is an important target structure for tumor‐specific imaging and therapy as this receptor subtype is overexpressed in very high density and incidence especially in human breast cancer. Targeting this receptor with radiolabeled truncated analogues of the endogenous ligand NPY (neuropeptide Y) has, however, not yet resulted in satisfactory imaging results when using positron emission tomography (PET). This can be attributed to the limited stability of these PET imaging agents caused by their fast proteolytic degradation. Although highly promising NPY analogues were developed, their stability has only been investigated in very few cases. In this systematical work, we comparatively determined the stability of the five most promising truncated analogues of NPY that were developed over the last years, showing the highest receptor affinities and subtype selectivities. The stability of the peptides was assessed in human serum as well as in a human liver microsomal stability assay; these gave complementary results, thus demonstrating the necessity to perform both assays and not just conventional serum stability testing. Of the tested peptides, only [Lys(lauroyl)27,Pro30,Lys(DOTA)31,Bip32,Leu34]NPY27‐36 showed high stability against peptidase degradation; thus this is the best‐suited truncated NPY analogue for the development of NPY(Y1)R‐specific imaging agents. Precise prediction: The stability of the five most promising truncated analogues of NPY that were developed over the last years has been assessed. Of these, only [Lys(lauroyl)27,Pro30,Lys(DOTA)31,Bip32,Leu34]NPY27‐36 showed a high stability against peptidase degradation by human serum and human liver peptidases, thus representing the best‐suited truncated NPY analogue for the development of NPY(Y1)R‐specific imaging agents.