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Abstract
BackgroundFolate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). In rheumatoid arthritis, FRβ is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [18F]fluoro-PEG-folate. The purpose of this study was to examine whether this folate tracer can also be used to monitor therapeutic efficacy of MTX in arthritic rats.MethodsArthritic rats received either no treatment or MTX therapy (1 mg/kg, either 2× or 4×). Healthy rats did not receive any arthritic induction or therapy. [18F]fluoro-PEG-folate PET-CT scans (60 min) were performed before and after MTX therapy. Following PET, the ex-vivo tissue distribution of radioactivity was determined in excised knees and multiple tissues. Synovial macrophage infiltration in knee sections was quantified by immunohistochemistry using ED1 and ED2 antibodies.ResultsPET scans clearly visualized increased uptake of [18F]fluoro-PEG-folate in arthritic knees compared with contralateral knees. Significantly lower standard uptake values (1.5-fold, p < 0.01) were observed in arthritic knees of both MTX-treated groups after therapy, approximating the levels seen in healthy rats. Consistently, ex-vivo tissue distribution demonstrated a 2–4-fold lower tracer uptake in the arthritic knee of 2× and 4× MTX-treated rats, respectively, compared with control rats. These results were corroborated with significantly reduced (2–4-fold, p < 0.01) ED1-positive and ED2-positive synovial macrophages in arthritic knees of the MTX-treated rats compared with those of the control rats.ConclusionThis study in arthritic rats underscores the potential and usefulness of [18F]fluoro-PEG-folate PET as a therapeutic monitoring tool of MTX therapy and potentially other anti-folate treatment of arthritis.
Highlights
Folate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX))
Chandrupatla et al Arthritis Research & Therapy (2017) 19:114 interesting properties for targeting with folate-based positron emission tomography (PET) tracers; for example, easy accessibility as an extracellular GPI-anchored membrane protein, high binding affinities for folates, and specific expression on activated macrophages in inflammatory diseases, allowing receptor targeting for imaging with folate-based PET tracers [9, 10]
Beyond successful application of single-photon imaging agents— for example, EC20, a 99mTc-labelled folate [23,24,25]—to image arthritis, recently a folate-based PET tracer, [18F]fluoro-Polyethylene glycol (PEG)-folate, has been synthesized [26]. Such a tracer could potentially employ the higher sensitivity of PET and its ability to quantify uptake, which is essential for intervention studies
Summary
Folate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). FRβ is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [18F]fluoro-PEG-folate. Beyond successful application of single-photon imaging agents— for example, EC20, a 99mTc-labelled folate [23,24,25]—to image arthritis, recently a folate-based PET tracer, [18F]fluoro-PEG-folate, has been synthesized [26]. Such a tracer could potentially employ the higher sensitivity of PET and its ability to quantify uptake, which is essential for intervention studies. The potential of [18F]fluoro-PEG-folate to monitor the efficacy of therapeutic interventions, in particular using anti-folates, such as MTX, has not been explored
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