68Ga-HBED-CC-WL-12 PET in Diagnosing and Differentiating Pancreatic Cancers in Murine Models

Abstract

Positron emission tomography (PET) has been proven as an important technology to detect the expression of programmed death ligand 1 (PD-L1) non-invasively and in real time. As a PD-L1 inhibitor, small peptide WL12 has shown great potential in serving as a targeting molecule to guide PD-L1 blockade therapy in clinic. In this study, WL12 was modified with HBED-CC to label 68Ga in a modified procedure, and the biologic properties were evaluated in vitro and in vivo. 68Ga-HBED-CC-WL12 showed good stability in saline and can specifically target PD-L1-positive cells U87MG and PANC02. In PANC02-bearing mice, 68Ga-HBED-CC-WL12 showed fast permeation in subcutaneous tumors within 20 min (SUVmax 0.37) and was of higher uptake in 90 min (SUVmax 0.38). When compared with 18F-FDG, 68Ga-FAPI-04, and 68Ga-RGD, 68Ga-HBED-CC-WL12 also demonstrated great image quality and advantages in evaluating immune microenvironment. This study modified the 68Ga-labeling procedure of WL12 and obtained better biologic properties and further manifested the clinical potential of 68Ga-HBED-CC-WL12 for PET imaging and guiding for immunotherapy.

Sensitive Positron Emission Tomography Imaging of PD-L1 Expression in Human Breast and Lung Carcinoma Xenografts Using the Radiometalated Peptide Ga-68-TRAP-WL12

“…Routine automated 68 Ga labeling was done as described above, and a log D 7.4 of −1.66 ± 0.08 ( n = 8) for 68 Ga-DOTA-WL12 was determined by shake-flask. Dynamic PET imaging in MDA-MB-231 xenografts revealed that similar to radiometalated WL12 conjugates comprising DOTAGA, , NOTA, HBED, or the respective radiofluorinated derivatives, 68 Ga-DOTA-WL12 showed a high and persistent uptake in the liver and a slow and incomplete blood clearance within the monitored time period of 90 min (Figure a). In contrast, 68 Ga-TRAP-WL12 was cleared much more rapidly from the blood and liver (Figure a).…”

“…A cyclic peptide referred to as WL12 was one of the first reported nonprotein ligands for PD-L1 . In line with established strategies of radiotracer development, this peptide has been functionalized with various moieties comprising positron-emitting radionuclides ( 18 F, 64 Cu, 68 Ga) on the terminal amine of an ornithine side chain. − These labels did not compromise its PD-L1 activity, suggesting that radiolabeled WL12 congeners indeed hold great promise as radiopharmaceuticals for in vivo mapping of PD-L1. However, the hitherto reported WL12-based positron emission tomography (PET) tracers showed an unsatisfactory performance in preclinical imaging experiments using tumor-xenografted mice.…”

Navigating the landscape of PD-1/PD-L1 imaging tracers: from challenges to opportunities

“…[ 68 Ga]Ga-NOTA-WL-12 uptake in the liver increased substantially and shifted toward the small intestines after adding WL-12 blocking ( 195 ). The group continues exploring ways to optimize the biological properties of this peptide-derived radiotracer further by testing other chelators, such as HBED-CC ( 196 ). Besides the initial study performed by Chatterjee et al ( 189 ), no further studies to elucidate structural features of the peptide have been conducted yet.…”

Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors

“…Nuclear medicine molecular imaging, especially positron emission tomography (PET), showed significant benefits for the quantification of proteins and biochemical processes in vivo , including its high sensitivity, whole-body imaging, and noninvasiveness. , Currently, many PD-L1 PET imaging tracers based on antibodies, nanobodies, and peptides have been studied with promising applications in preclinical investigations, which demonstrated the power of PET imaging for the noninvasive quantification of PD-L1 expression. For example, 18 F-BMS986192, , 89 Zr-atezolizumab, , 68 Ga-W12, , and so many other radiotracers showed good clinical responses of immunotherapy in tumor patients correlated with PET imaging, even better than with immunohistochemistry for some tracers . However, there are still big challenges, including long metabolic half-life, instability, and high cost, for using these tracers.…”