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Identification of a Suitable Peptidic Molecular Platform for the Development of NPY(Y1 )R-Specific Imaging Agents
Korbinian Krieger1, Björn Wängler2, Ralf Schirrmacher3
1Biomedical Chemistry Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
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.
Insights
Researchers evaluated neuropeptide Y (NPY) analogues for breast cancer imaging. One analogue, [Lys(lauroyl)27 ,Pro30 ,Lys(DOTA)31 ,Bip32 ,Leu34 ]NPY27-36, demonstrated superior stability for developing NPY(Y1 )R-specific imaging agents.
Area of Science:
- Biochemistry
- Molecular Biology
- Radiopharmaceutical Chemistry
Background:
- Neuropeptide Y receptor 1 (NPY(Y1 )R) is overexpressed in human breast cancer, making it a key target for tumor imaging and therapy.
- Current positron emission tomography (PET) imaging agents targeting NPY(Y1 )R using radiolabeled NPY analogues suffer from limited stability due to proteolytic degradation.
- Previous studies have not systematically investigated the stability of promising NPY analogues, hindering the development of effective imaging agents.
Purpose of the Study:
- To systematically compare the stability of the five most promising truncated NPY analogues with high receptor affinity and subtype selectivity.
- To identify the most stable NPY analogue suitable for developing NPY(Y1 )R-specific PET imaging agents for breast cancer.
- To evaluate the necessity of using both human serum and human liver microsomal assays for comprehensive peptide stability assessment.
Main Methods:
- Comparative stability assessment of five truncated NPY analogues in human serum.
- Evaluation of peptide stability using a human liver microsomal assay.
- Determination of receptor affinities and subtype selectivities for the NPY analogues.
Main Results:
- Only one analogue, [Lys(lauroyl)27 ,Pro30 ,Lys(DOTA)31 ,Bip32 ,Leu34 ]NPY27-36, exhibited high stability against peptidase degradation in both serum and microsomal assays.
- Human serum and liver microsomal assays provided complementary stability data, highlighting the importance of employing both methods.
- The selected analogue demonstrated superior stability compared to other tested NPY analogues.
Conclusions:
- The truncated NPY analogue [Lys(lauroyl)27 ,Pro30 ,Lys(DOTA)31 ,Bip32 ,Leu34 ]NPY27-36 is the most promising candidate for developing stable and effective NPY(Y1 )R-specific imaging agents.
- Comprehensive stability testing using both serum and liver microsomal assays is crucial for validating peptide-based imaging agents.
- This finding advances the development of targeted breast cancer imaging and potentially therapy.
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