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Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [⁶⁸Ga]MHLL1.

ABSTRACT: 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.

SUBMITTER: Langer LBN

PROVIDER: S-EPMC8315078 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new 68Ga-labeled FAP inhibitor (68Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. Methods: MI and sham-operated rats were scanned with 68Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with 18F-FDG (3 d after MI). Dynamic 68Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Results: 68Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased 18F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that 68Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Conclusion: 68Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.

Project description:PET imaging that targets fibroblast activation protein (FAP) on the surface of cancer-associated fibroblasts has yielded promising tumor diagnostic results. FAP-2286 contains cyclic peptides as FAP-binding motifs to optimize tumor retention compared with the small-molecule FAP inhibitor (FAPI) series (FAPI-04/46). The aim of this study was to evaluate the diagnostic accuracy of 68Ga-FAP-2286 to detect primary and metastatic lesions in patients with various types of cancer, compared with 18F-FDG and 68Ga-FAP-2286. Methods: Sixty-four patients with 15 types of cancer underwent 68Ga-FAP-2286 PET/CT for initial assessment or detection of recurrence. For comparison, 63 patients underwent paired 68Ga-FAP-2286 and 18F-FDG PET/CT and 19 patients underwent paired 68Ga-FAP-2286 and 68Ga-FAPI-46 PET/CT. Lesion uptake was quantified as SUVmax and tumor-to-background ratio. The Wilcoxon matched-pairs signed-rank test was used to compare SUVmax between PET modalities, and the McNemar test was used to compare lesion detectability. Results: Uptake of 68Ga-FAP-2286 was significantly higher than that of 18F-FDG in primary tumors (median SUVmax, 11.1 vs. 6.9; P < 0.001), lymph node metastases (median SUVmax, 10.6 vs. 6.2; P < 0.001), and distant metastases, resulting in improved image contrast and lesion detectability. All primary tumors (46/46) were clearly visualized by 68Ga-FAP-2286 PET/CT, whereas 9 of the 46 lesions could not be visualized by 18F-FDG PET/CT. The lesion detection rate of 68Ga-FAP-2286 PET/CT was superior to that of 18F-FDG PET/CT for involved lymph nodes (98% [105/107] vs. 85% [91/107], P = 0.001) and bone and visceral metastases (95% [162/171] vs. 67% [114/171], P < 0.001). 68Ga-FAP-2286 yielded tumor uptake and lesion detection rates similar to those of 68Ga-FAPI-46 in a subcohort of 19 patients. Conclusion: 68Ga-FAP-2286 is a promising FAP-inhibitor derivative for safe cancer diagnosis, staging, and restaging. It may be a better alternative to 18F-FDG for the cancer types that exhibit low-to-moderate uptake of 18F-FDG, which include gastric, pancreatic, and hepatic cancers. In addition, 68Ga-FAP-2286 and 68Ga-FAPI-46 yielded comparable clinical results.

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Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [⁶⁸Ga]MHLL1.

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Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [68Ga]MHLL1.

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Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [⁶⁸Ga]MHLL1.