PET Imaging of T Cells: Target Identification and Feasibility Assessment

Area of Science:

• Immunology
• Oncology
• Molecular Imaging

Background:

• Positron emission tomography (PET) imaging of T-cells offers significant potential for diagnosing and monitoring patients in immunology and oncology.
• Currently, there is a lack of suitable molecular targets for developing effective T-cell PET imaging agents.

Purpose of the Study:

• To explore potential target proteins selectively expressed in T-cells for PET imaging agent development.
• To identify and evaluate lead molecules targeting proteins such as protein kinase C isozyme θ (PKCθ), lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase 70 (ZAP70), and interleukin-2-inducible T-cell kinase (Itk).

Main Methods:

• Screened multiple T-cell-specific target proteins with available lead molecules.
• Focused on Itk as a promising target.
• Synthesized and characterized a tool molecule, compound (23), for in vivo T-cell imaging.

Main Results:

• Identified a tool molecule, (5aR)-5,5-difluoro-5a-methyl-N-(1-((S)-3-(methylsulfonyl)phenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide (23), with properties suitable for in vivo T-cell imaging.
• The developed molecule, while not optimal for clinical use, demonstrates proof-of-concept for targeting Itk.

Conclusions:

• It is feasible to develop selective PET ligands targeting Itk for imaging T-cell distribution in patients.
• Further optimization of Itk-targeting molecules is warranted for clinical application in T-cell PET imaging.