Natural Selection-Guided ACE2-Targeted Molecular Imaging: A New Paradigm for PET Tracer Development

Area of Science:

• Biomedical Imaging
• Molecular Biology
• Drug Discovery

Background:

• Angiotensin-converting enzyme 2 (ACE2) is a critical biomarker and therapeutic target for various diseases.
• Noninvasive in vivo visualization of ACE2 is essential for disease management and treatment evaluation.

Purpose of the Study:

• To develop a high-affinity peptide targeting molecule for ACE2.
• To enable noninvasive PET imaging for ACE2 mapping and assessment of related diseases.

Main Methods:

• Screening of RBD peptide libraries from Omicron variants (BA.1, BA.2, BA.5) using radioimmunoassay.
• High-throughput screening based on binding to HEK293-hACE2 cells and molecular docking verification.
• Development of SPECT and PET imaging tracers (¹²⁵I-Omi-X and ⁶⁸Ga-DOTA-Omi-X) for biodistribution and in vivo ACE2 mapping.

Main Results:

• Identified Omi-X (⁵⁰⁵HQPYRVVVLSFELLH⁵¹⁹) with superior ACE2 binding affinity.
• ¹²⁵I-labeled Omi-X demonstrated high ACE2 specificity and retention in SPECT imaging of K18-hACE2 mice.
• ⁶⁸Ga-DOTA-Omi-X enabled successful ACE2-targeted PET imaging, applicable to RAAS-related diseases like cardiac hypertrophy.

Conclusions:

• The Omi-X peptide serves as an effective tool for noninvasive ACE2 visualization and mapping.
• This approach provides a paradigm for developing targeted therapies by leveraging viral-host adaptation.
• The developed imaging tracers offer valuable tools for investigating RAAS pathophysiology and precision diagnostics.