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Activation of the adenosine 2A receptor (A 2A R) can lead to tumor immunosuppression, which results in poor prognosis of immunotherapy. The aim of this study was to design novel 18 F-labeled probes ([ 18 F]F-PFP 2 and [ 18 F]F-PFP 4 ) to visualize A 2A R in the tumor. The uptake of radioprobes in A 2A R-negative 4T1 breast tumor was lower than that of A 2A R-positive B16F10 melanoma at 1 h p.i. (1.22 ± 0.36% ID/g vs 2.80 ± 0.72% ID/g), 2 h p.i. (1.09 ± 0.20% ID/g vs 2.93 ± 0.76% ID/g) and 3 h p.i. (0.89 ± 0.27% ID/g vs 2.73 ± 0.58% ID/g), respectively. B16F10 lung metastasis models were employed to expand the application scenarios, observing significantly higher uptake of [ 18 F]F-PFP 2 in metastatic lesions compared to normal lung tissue (5.55 ± 2.18% ID/g vs 1.89 ± 0.65% ID/g, tumor/lung ratio ∼3). It is given that [ 18 F]F-PFP 2 might lay the foundation for establishing an A 2A R-targeted imaging evaluation system for tumors, which will provide more precise guidance for personalized treatment.

Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99m Tc-labeled dimeric HF 2 with high tumor uptake and image contrast. The dimeric HF 2 was synthesized and radiolabeled with 99m Tc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [ 99m Tc]Tc-TPPTS-HF 2 , [ 99m Tc]Tc-EDDA-HF 2 , and [ 99m Tc]Tc-TPPMS-HF 2 dimers. SPECT imaging results indicated that [ 99m Tc]Tc-TPPTS-HF 2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [ 99m Tc]Tc-EDDA-HF 2 and [ 99m Tc]Tc-TPPMS-HF 2 . Notably, [ 99m Tc]Tc-TPPTS-HF 2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [ 99m Tc]Tc-TPPTS-HF. Moreover, [ 99m Tc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99m Tc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [ 99m Tc]Tc-TPPTS-HF 2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.

Due to the complex heterogeneity in different cancer types, the heterodimeric strategy has been intensively practiced to improve the effectiveness of tumor diagnostics. In this study, we developed a series of novel 18 F-labeled biotin/FAPI-conjugated heterobivalent radioligands ([ 18 F]AlF-NSFB, [ 18 F]AlF-NSFBP 2 , and [ 18 F]AlF-NSFBP 4 ), synergistically targeting both fibroblast activation protein (FAP) and biotin receptor (BR), to enhance specific tumor uptake and retention. The in vitro and in vivo biological properties of these dual-targeting tracers were evaluated, with a particular focus on positron emission tomography imaging in A549 and HT1080-FAP tumor-bearing mice. Notably, in comparison to the corresponding FAP-targeted monomer [ 18 F]AlF-NSF, biotin/FAPI-conjugated heterodimers exhibited a high uptake in tumor and prolong retention. In conclusion, as a proof-of-concept study, the findings validated the superiority of biotin/FAPI-conjugated heterodimers and the positive influence of biotin and linker on pharmacokinetics of radioligands. Within them, the bispecific [ 18 F]AlF-NSFBP 4 holds significant promise as a candidate for further clinical translational studies.

The stimulator of interferon genes (STING) is a vital protein to the immune surveillance of the tumor microenvironment. In this study, we develop novel inhibitor-based radioligands and evaluate their feasibility for noninvasive visualization of STING expression in tumor-bearing mice. Analogous compounds to STING inhibitors C170 and C176 were synthesized and labeled with 131 I and 18 F to attain [ 131 I]I-NFIP and [ 18 F]F-NFEP, respectively. The radiosynthesis was achieved with high radiochemical purity (>95%) and molar activity (28.56-48.89 GBq/μmol). The affinity and specificity of tracers were assessed through cell uptake and docking experiments, demonstrating that [ 131 I]I-NFIP exhibited high specificity for STING, with a cell-based IC 50 value of 7.56 nM. Small-animal PET/SPECT imaging and biodistribution studies in tumor-bearing mice models were performed to verify the tracers' pharmacokinetics and tumor-targeting capabilities ( n = 3/group). SPECT imaging demonstrated that [ 131 I]I-NFIP rapidly accumulated in the Panc02 tumor quickly at 30 min post-injection, with a tumor-to-muscle (T/M) ratio of 2.03 ± 0.30. This ratio significantly decreased in the blocking group (1.10 ± 0.14, ** P < 0.01, n = 3). Furthermore, tumor uptake and the T/M ratio of [ 131 I]I-NFIP were positively associated with STING expression. In summary, [ 131 I]I-NFIP is the first STING-specific inhibitor-based radioligand offering the potential for visualizing STING status in tumors., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The stimulator of interferon genes (STING) is pivotal in mediating STING-dependent type I interferon production, which is crucial for enhancing tumor rejection. Visualizing STING within the tumor microenvironment is valuable for STING-related treatments, yet the availability of suitable STING imaging probes is limited. In this study, we developed [ 18 F]AlF-ABI, a novel 18 F-labeled agent featuring an amidobenzimidazole core structure, for positron emission tomography (PET) imaging of STING in B16F10 and CT26 tumors. [ 18 F]AlF-ABI was synthesized with a decay-corrected radiochemical yield of 38.0 ± 7.9% and radiochemical purity exceeding 97%. The probe exhibited a nanomolar STING binding affinity ( K D = 35.6 nM). Upon administration, [ 18 F]AlF-ABI rapidly accumulated at tumor sites, demonstrating significantly higher uptake in B16F10 tumors compared to CT26 tumors, consistent with STING immunofluorescence patterns. Specificity was further validated through in vitro cell experiments and in vivo blocking PET imaging. These findings suggest that [ 18 F]AlF-ABI holds promise as an effective agent for visualizing STING in the tumor microenvironment.

Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH 2 (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with 68 Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with 68 Ga, its dual-receptor-binding affinity was evaluated in vitro and in vivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of 68 Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of 18 F-FDG. Results: 68 Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of 68 Ga-FAPI-LM3 was significantly higher than that of 68 Ga-FAPI-46 and 68 Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, 68 Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did 18 F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: 68 Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both in vitro and in vivo, resulting in improved tumor uptake and retention compared with that observed with monomeric 68 Ga-FAPI and 68 Ga-DOTA-LM3. This study highlights the clinical feasibility of 68 Ga-FAPI-LM3 PET/CT for NPC imaging., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)