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Updated: Jul 1, 2026
Harnessing the Bioorthogonal Inverse Electron Demand Diels-Alder Cycloaddition for Pretargeted PET Imaging
Published on: February 3, 2015
Targeting of VISTA with Cyclic Peptide-Based PET Tracers for Immune Checkpoint Imaging
Han Feng1, Xiaoting Tian1, Xiaofei Li2
1Department of Pharmacy, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
Abstract:
Given the distinct roles of VISTA in immune regulation, a better visualization of VISTA expression could clarify the tumor immune status and predict the responses to immunotherapy. However, only a few targeted probes are in development and insufficient to fulfill clinical demands. In this study, based on cyclic peptide antagonist AP1049, three novel radiotracers, [68Ga]Ga-AP1049, [68Ga]Ga-AHX-AP1049, and [68Ga]Ga-Pip-AP1049, were designed and developed for targeting and imaging VISTA in cancers. Molecular dynamics simulation revealed the better binding of NOTA-Pip-AP1049 for VISTA protein than that of NOTA-AP1049 and NOTA-AHX-AP1049. Protein binding assays demonstrated their high specificity and affinity with IC50 values of 58.10, 23.34, and 17.56 nM, respectively. The B16-F10 tumor uptake of three tracers was significant and decreased over time within 120 min, with tumor uptake values of 1.02 ± 0.21, 1.56 ± 0.21, and 1.89 ± 0.29 %ID/cc and tumor/muscle ratios of 2.36 ± 0.36, 3.10 ± 0.51, and 4.06 ± 0.71 at 30 min post-injection, respectively. Their in vivo specificity were verified by blocking studies. Furthermore, [68Ga]Ga-Pip-AP1049 PET could detect varying VISTA expression in B16-F10, 4T1, MC38, and CT26 xenograft models with tumor uptake values of 2.71 ± 0.43, 2.32 ± 0.44, 1.17 ± 0.30, and 0.85 ± 0.17 %ID/cc, which were in consistent with percentages of VISTA+ cells (r = 0.8712, P < 0.0001). Biodistribution data suggested their renal excretion and favorable pharmacokinetics. In conclusion, [68Ga]Ga-Pip-AP1049 is a promising tracer for PET imaging of VISTA expression in tumor microenvironment, indicating its potential as a companion diagnostic of immunotherapy.
Insights
Researchers developed novel radiotracers to visualize VISTA expression for predicting cancer immunotherapy response. [68Ga]Ga-Pip-AP1049 demonstrated superior binding and imaging capabilities, showing potential as a companion diagnostic.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
- Molecular Imaging
Background:
- VISTA plays a crucial role in immune regulation within the tumor microenvironment.
- Accurate visualization of VISTA expression is essential for predicting immunotherapy outcomes.
- Current VISTA-targeted probes are limited, necessitating the development of new imaging agents.
Purpose of the Study:
- To design and develop novel radiotracers for targeting and imaging VISTA in cancers.
- To evaluate the binding affinity, specificity, and in vivo performance of the developed tracers.
- To assess the potential of these tracers as companion diagnostics for cancer immunotherapy.
Main Methods:
- Cyclic peptide antagonist AP1049 was used as a basis for designing three novel radiotracers: [68Ga]Ga-AP1049, [68Ga]Ga-AHX-AP1049, and [68Ga]Ga-Pip-AP1049.
- Molecular dynamics simulations and protein binding assays were performed to assess binding affinity and specificity.
- In vivo studies using xenograft tumor models evaluated tracer uptake, biodistribution, and pharmacokinetic properties.
- Positron Emission Tomography (PET) imaging was employed to visualize VISTA expression in different cancer models.
Main Results:
- [68Ga]Ga-Pip-AP1049 exhibited superior binding affinity (IC50 = 17.56 nM) and molecular dynamics simulation results compared to the other two tracers.
- All three tracers showed significant tumor uptake in B16-F10 xenografts, with [68Ga]Ga-Pip-AP1049 demonstrating the highest tumor-to-muscle ratios.
- In vivo specificity was confirmed by blocking studies, and [68Ga]Ga-Pip-AP1049 successfully visualized varying VISTA expression across different cancer models, correlating well with VISTA+ cell percentages (r=0.8712).
- Biodistribution data indicated favorable renal excretion and pharmacokinetics for the tracers.
Conclusions:
- [68Ga]Ga-Pip-AP1049 is a highly promising PET tracer for imaging VISTA expression in the tumor microenvironment.
- This novel radiotracer holds significant potential as a companion diagnostic tool to guide and predict responses to cancer immunotherapy.
- The developed tracers offer improved capabilities for assessing tumor immune status and guiding therapeutic strategies.
