PESIN Conjugates for Multimodal Imaging: Can Multimerization Compensate Charge Influences on Cell Binding Properties?...

Area of Science:

• Radiochemistry
• Molecular Imaging
• Medicinal Chemistry

Background:

• Anionic charges negatively impact in vitro gastrin-releasing peptide receptor (GRPR) binding of labeled peptide dimers.
• The effect of peptide multimerization valency on GRPR binding affinities remains underexplored.

Purpose of the Study:

• To investigate if increased peptide valency can mitigate the adverse effects of negative charges on GRPR binding.
• To design and synthesize novel multimodal imaging units (MIUs) with varying peptide valencies.

Main Methods:

• Designed hybrid MIUs with one or two click chemistry functional groups.
• Synthesized peptide homodimers and homotetramers using PESIN (PEG3-BBN7-14) and MIUs.
• Evaluated photophysical properties, radiolabeling efficiency (68Ga, 64Cu), hydrophilicity, and GRPR binding affinities (IC50).

Main Results:

• Hydrophilicity and GRPR binding affinities were influenced by negative charges and peptide copy number.
• Homodimers showed logP = -2.2 ± 0.1 and IC50 = 59.1 ± 1.5 nM.
• Homotetramers showed logP = -1.9 ± 0.1 and IC50 = 99.8 ± 3.2 nM.

Conclusions:

• Increased peptide valency in dually labeled PESIN multimers can partially compensate for the negative influence of charged building blocks on GRPR binding.
• Molecular design and the number of peptide binding motives are crucial for optimizing GRPR affinities in multimodal imaging agents.