ObjectivesTo date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease.MethodsIn this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data.ResultsUsing combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions.ConclusionFAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
Click for PET: An efficient strategy based on click chemistry has been developed for 18F‐labeling alkyne‐bearing peptides with concomitant glycosylation. The mild conditions and general applicability of this reliable reaction gives access to a new class of 18F‐glycopeptide radiopharmaceuticals with improved biological properties for in vivo imaging studies by positron emission tomography (PET).
Glycosylation frequently improves the biokinetics and clearance properties of macromolecules in vivo and could therefore be used for the design of radiopharmaceuticals for positron emission tomography (PET). Recently, we have developed a click chemistry method for (18)F-fluoroglycosylation of alkyne-bearing RGD-peptides targeting the integrin receptor. To investigate whether this strategy could yield an (18)F-labeled RGD glycopeptide with favorable biokinetics, we generated a series of new RGD glycopeptides, varying the 6-fluoroglycosyl residue from monosaccharide to disaccharide units, which provided the glucosyl ([(19)F]6Glc-RGD, 4b), galactosyl ([(19)F]Gal-RGD, 4c), maltosyl ([(19)F]Mlt-RGD, 4e), and cellobiosyl ([(19)F]Cel-RGD, 4f) conjugated peptides in high yields and purities of >97%. All of these RGD glycopeptides showed high affinity to αvβ3 (11-55 nM), αvβ5 (6-14 nM), and to αvβ3-positive U87MG cells (90-395 nM). (18)F-labeling of the various carbohydrate precursors (1a-f) using cryptate-assisted reaction conditions (CH3CN, 85 °C, 10 min) gave (18)F-labeled glycosyl azides in radiochemical yields (RCYs) of up to 84% ([(18)F]2b). The deacetylation and subsequent click reaction with the alkyne-bearing cyclic RGD peptide proceeded in one-pot reactions with RCYs as high as 81% in 15-20 min at 60 °C, using a minimal amount of peptide precursor (100 nmol). Optimization of the radiosynthesis strategy gave a decay-uncorrected RCY of 16-24% after 70-75 min (based on [(18)F]fluoride). Due to their high-yield radiosyntheses, the glycopeptides [(18)F]6Glc-RGD and [(18)F]Mlt-RGD were chosen for comparative biodistribution studies and dynamic small-animal PET imaging using U87MG tumor-bearing nude mice. [(18)F]6Glc-RGD and [(18)F]Mlt-RGD showed significantly decreased liver and kidney uptake by PET relative to the 2-[(18)F]fluoroglucosyl analog [(18)F]2Glc-RGD, and showed specific tumor uptake in vivo. Notably, [(18)F]Mlt-RGD revealed uptake and retention in the U87MG tumor comparable to that of [(18)F]Galacto-RGD. Both [(18)F]6Glc-RGD and [(18)F]Mlt-RGD were obtained by a reliable and easy click chemistry-based procedure, much more rapidly than was [(18)F]Galacto-RGD. Due to its favorable biodistribution and tissue clearance in vivo, [(18)F]Mlt-RGD represents a viable alternative radiotracer for imaging integrin expression in solid tumors by PET.
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