86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis

Ding, Jie; Xu, Mengxin; Chen, Junyi; Zhang, Pu; Huo, Li; Kong, Ziren; Liu, Zhibo

doi:10.1021/acs.molpharmaceut.2c00579

Cited by 11 publications

(8 citation statements)

References 50 publications

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“…This is because faster clearance from the blood pool reduces their chances to bind to FAP in tumors and might result in a relatively lower overall tumor uptake. This could be solved by the addition of an albumin binder to the pyridine-based FAP-targeted ligands to extend their blood residence time as similar approaches have been exploited to Increase the tumor uptake of radiolabeled quinoline-based FAPI-04 derivatives [ 34 , 35 ]. However, the blood residence time needs to be carefully adjusted as staying to long in blood will result in hematological toxicity.…”

Section: Discussionmentioning

confidence: 99%

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

et al. 2023

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Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop 68Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [68Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC50(FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [68Ga]Ga-AV02053 and [68Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [68Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [68Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [68Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [68Ga]Ga-AV02070 and [68Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [68Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast.

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Section: Discussionmentioning

confidence: 99%

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

et al. 2023

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“…Improving the target-to-non target ratio of tumor imaging, reducing the toxic side effects of normal tissues, and increasing the therapeutic efficiency of tumors are important goals for the development of FAP-targeted radiopharmaceuticals. By introducing albumin binder moieties or PEG side chains, ,− increasing the number of target molecules, ,− conjugating with other target molecules, and using peptide structures as alternative target molecules, the short tumor residence time and low target-to-nontarget ratio of [ 68 Ga]FAPI04 was optimized, which greatly improved the application of FAP-targeted radiopharmaceuticals in tumor diagnosis and treatment. A series of related tumor diagnosis and treatment clinical trials was carried out.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of ¹⁸F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging

Yu,

Huang,

Chen

et al. 2023

ACS Pharmacol. Transl. Sci.

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Fibroblast activation protein (FAP) is closely related to central nervous system diseases such as stroke and brain tumors, but PET tracers that can be used for brain imaging have not been reported. Here, we designed, synthesized, and evaluated 18F-labeled UAMC1110 derivatives suitable for brain imaging targeting FAP. By substituting the F atom for the H atom on the aromatic ring of compound UAMC1110, 1a–c were designed and prepared. 1a–c were confirmed to have a high affinity for FAP through molecular docking and enzyme assay. [ 18 F]1a–c were successfully prepared and confirmed to have high affinity. The stability in vivo indicates that no obvious metabolites of [ 18 F]1a,b were found in the plasma 1 h after injection, which is beneficial for brain imaging. In vitro cell uptake experiments showed that [ 18 F]1a,b and [68Ga]FAPI04 exhibited similar uptake and internalization rates. PET imaging of U87MG subcutaneous tumor showed that [ 18 F]1a,b could penetrate the blood–brain barrier with higher uptake and longer retention time than [68Ga]FAPI04 (uptake at 62.5 min, 1.06 ± 0.23, 1.09 ± 0.25% ID/g vs 0.21 ± 0.10% ID/g, respectively). The brain-to-blood ratios of [ 18 F]1a,b were better than [68Ga]FAPI04. Biodistribution and PET imaging showed that [ 18 F]1a had better uptake on tumors and a higher tumor-to-muscle ratio than [ 18 F]1b and [68Ga]FAPI04. Further imaging of U87MG intracranial glioma showed that [ 18 F]1a outlined high-contrast gliomas in a short period of time compared to [ 18 F]1b. Therefore, [ 18 F]1a is expected to be useful in the diagnosis of FAP-related brain diseases.

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“…Other, 68 Ga- and 177 Lu-bound FAP albumin-binding ligands are under development [ 557 ]. Of four albumin-binding FAPIs (TE-FAPI-01 to 04) labeled with 68 Ga, Yttrium-86 ( 86 Y), and 177 Lu, TE-FAPI-04 had the most favorable performance with respect to in vitro stability, binding affinity, in vivo biodistribution, pharmacokinetics, tumor uptake, labeling, and imaging [ 558 ].…”

Section: Cancer Stroma As a Therapeutic Targetmentioning

confidence: 99%

Fibroblasts as Turned Agents in Cancer Progression

Wieder

2023

Cancers

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Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer “wounds” the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.

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86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis

Cited by 11 publications

References 50 publications

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

Design, Synthesis, and Evaluation of ¹⁸F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging

Fibroblasts as Turned Agents in Cancer Progression

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86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis

Cited by 11 publications

References 50 publications

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

Design, Synthesis, and Evaluation of 18F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging

Fibroblasts as Turned Agents in Cancer Progression

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Design, Synthesis, and Evaluation of ¹⁸F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging