Synthesis and Biological Evaluation of Novel ^99mTc-Tricarbonyl-Labeled Small-Molecule SPECT Tracers for PD-L1 Imaging

Area of Science:

• Nuclear medicine
• Radiochemistry
• Molecular imaging

Background:

• Radiotracers are crucial for evaluating programmed death protein ligand 1 (PD-L1) expression to guide cancer immunotherapy.
• Developing metallic radionuclide-labeled radiotracers for PD-L1 is challenging due to complex interactions with PD-L1 dimers.

Purpose of the Study:

• To design and synthesize novel 99mTc-labeled radiotracers for PD-L1 imaging.
• To investigate the influence of scaffold and polar tail chain length on radiotracer-PD-L1 interaction.

Main Methods:

• Synthesis of novel 99mTc-labeled radiotracers using an integrated strategy.
• Modification of scaffold and polar tail chain lengths.
• In vivo biodistribution studies.
• Molecular docking simulations.

Main Results:

• The scaffold minimally affected PD-L1 affinity but significantly impacted in vivo pharmacokinetic properties.
• Both the core structure and polar tail chain length of the 99mTc-labeled radiotracers influenced interaction with PD-L1 dimers.
• Biodistribution and molecular docking supported the contribution of structural elements to PD-L1 binding.

Conclusions:

• The study successfully developed novel 99mTc-labeled radiotracers for PD-L1 imaging.
• Structural modifications offer a strategy to optimize radiotracer performance for guiding PD-1/PD-L1 inhibitor therapy.
• Findings provide insights into the structure-activity relationships for PD-L1 targeting radiotracers.