[⁶⁸Ga]Ga-RAYZ-8009: A Peptide PET Tracer for Targeting HCC in Humans

TO THE EDITOR: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for approximately 85% of cases (1). Morphologic imaging modalities, including ultrasound, CT, and MRI, are insufficient for differential diagnosis of hepatic lesions and detection of distant metastases (2). PET is more effective for whole-body scanning. However, the diagnostic efficacy of both ¹⁸F-FDG and fibroblast activation protein inhibitor PET for HCC is poor (3,4). Therefore, the development of more effective targeted diagnostic radiopharmaceuticals for HCC is urgently needed.

In a recent featured article of the month in The Journal of Nuclear Medicine (5), Poot et al. reported the first-in-human results of [⁶⁸Ga]Ga-RAYZ-8009 PET targeting glypican-3 (GPC3), which is a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan that is expressed in 75%–90% of HCCs (6). Previous preclinical studies have demonstrated the superior diagnostic accuracy of GPC3-targeted PET imaging in HCC mice models (7,8). In this study, [⁶⁸Ga]Ga-RAYZ-8009 was automatically produced by labeling the peptide precursor with satisfactory radiolabeling yields, the use of which greatly advanced GPC3-targeted PET for human HCCs (5). The results of the static and dynamic imaging demonstrate heterogeneity of the tracer uptake without correlations with the Liver Imaging Reporting and Data System and lesion size (5). As expected, high tumor accumulation of [⁶⁸Ga]Ga-RAYZ-8009 was revealed in GPC3-positive HCCs (5).

However, several aspects in this article have drawn our attention, which may negatively impact the comprehension on this study. For example, there is confusion about the data in Table 3. In 5 patients with PET acquisitions at 4 h after tracer administration, the median maximum tumor–to–healthy liver ratio (TLR) is 8.8, with a range from 3.8 to 4.9. The median mean TLR is 10.0, with a range from 41.4 to 56.9. Obviously, these medians appear out of range, thus the data remain unclear and to be corrected. Similarly, since the data of this study presented skewed distribution as described by the authors, continuous data should be expressed by the medians with either the range or interquartile range (9) rather than TLR averages (more than 7.5) of 50 lesions as exactly reported in the section of Static Imaging. Furthermore, in Figure 2, the mean values should have been accompanied by error bars.

The biopsy results described in Figure 3 failed to show the correspondence between GPC3 expression and tracer uptake, which should be expressed by microscopic immunohistochemistry. In addition, we are curious why the uptake in the stomach was so high at 30 min after administration, as shown in Figure 2; more detailed explanations of this phenomenon would be appreciated.

Taken together, the results of this study show that [⁶⁸Ga]Ga-RAYZ-8009 PET is promising for the diagnosis of patients with GPC3-positive HCC, which might be also helpful for the selection of certain patients with HCC to receive targeted anticancer therapies. We recommend that the authors provide the GPC3 immunohistochemistry results to support more rigorous conclusions. Future clinical trials are warranted to assess the potential of [⁶⁸Ga]Ga-RAYZ-8009 PET for improved diagnosis and staging of HCC. We also encourage the development of more targeted diagnostic or theranostic radiopharmaceuticals for intelligent precision medicine.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication December 5, 2024.
• Accepted for publication December 19, 2024.