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

Abstract

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.

Cysteine protecting groups: applications in peptide and protein science

“…42c), 280 and very recently in the synthesis of a disulfide containing, truncated neuropeptide Y (NPY) analogue. 281 5.10.13 Sec-isoamyl mercaptan (SIT) and 2-methyloxolane-3-thiol (MOT). 3-Methyl-2-butanethiol/sec-isoamyl mercaptan (SIT, Fig.…”

PET Imaging of the Neuropeptide Y System: A Systematic Review

“…Recently, Krieger et al have reported the synthesis of 68 Ga-radiolabeled analogues of the most promising previously described truncated NPY analogues and compared them regarding their metabolic stability [133]. Of the nearly 80 truncated peptides analogues of NPY that have been developed over the years, the authors chose the following five by virtue of their metabolic stability: linear [Pro 30 ,Lys(DOTA) 31 ,Tyr 32 68 Ga 3+ (which was obtained by the fractioned elution of an IGG 68 Ge/ 68 Ga generator system) in an aqueous acetate-buffered solution.…”