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Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

ABSTRACT: Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [¹¹¹In]QCP02, using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity in vivo. QCP01 and [¹¹¹In]QCP02 demonstrated nanomolar inhibition of FAP at K_i values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically in vivo. [¹¹¹In]QCP02 showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration.

SUBMITTER: Slania SL

PROVIDER: S-EPMC8214312 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

Slania Stephanie L SL Das Deepankar D Lisok Ala A Du Yong Y Jiang Zirui Z Mease Ronnie C RC Rowe Steven P SP Nimmagadda Sridhar S Yang Xing X Pomper Martin G MG

Journal of medicinal chemistry 20210317 7

Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [111In]QCP02, using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), pros ...[more]

PMID: 33730493

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Project description:Fibroblast activation protein (FAP) is regarded as a promising target for the diagnosis and treatment of tumors as it was overexpressed in cancer-associated fibroblasts. FAP inhibitors bearing a quinoline scaffold have been proven to show high affinity against FAP in vitro and in vivo, and the scaffold has been radio-labeled for the imaging and treatment of FAP-positive tumors. However, currently available FAP imaging agents both contain chelator groups to enable radio-metal labeling, making those tracers more hydrophilic and not suitable for the imaging of lesions in the brain. Herein, we report the synthesis, radio-labeling, and evaluation of a 18F-labeled quinoline analogue ([18F]3) as a potential FAP-targeted PET tracer, which holds the potential to be blood-brain barrier-permeable. [18F]3 was obtained by one-step radio-synthesis via a copper-mediated SNAR reaction from a corresponding boronic ester precursor. [18F]3 showed moderate lipophilicity with a log D 7.4 value of 1.11. In cell experiments, [18F]3 showed selective accumulation in A549-FAP and U87 cell lines and can be effectively blocked by the pre-treatment of a cold reference standard. Biodistribution studies indicated that [18F]3 was mainly excreted by hepatic clearance and urinary excretion, and it may be due to its moderate lipophilicity. In vivo PET imaging studies indicated [18F]3 showed selective accumulation in FAP-positive tumors, and specific binding was confirmed by blocking studies. However, low brain uptake was observed in biodistribution and PET imaging studies. Although our preliminary data indicated that [18F]3 holds the potential to be developed as a blood-brain barrier penetrable FAP-targeted PET tracer, its low brain uptake limits its application in the detection of brain lesions. Herein, we report the synthesis and evaluation of [18F]3 as a novel small-molecule FAPI-targeted PET tracer, and our results suggest further structural optimizations would be needed to develop a BBB-permeable PET tracer with this scaffold.

Project description:Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar. Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo. We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [68Ga]MHLL1 after acute MI. Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [68Ga]MHLL1. Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum. Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine. The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g). PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages. Results: [68Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208). In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance. At 7 d after coronary artery ligation, [68Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013). Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001). Autoradiography and histology confirmed the regional uptake of [68Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining. Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo. Conclusion: The simplified synthesis of [68Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI.

Dataset Information

Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

Publications

Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

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