Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [¹⁸F]Fluoro-PEG-Folate

Abstract

Background In rheumatoid arthritis, articular inflammation is a hallmark of disease, while the involvement of extra-articular tissues is less well defined. Here, we examined the feasibility of PET imaging with the macrophage tracer [18F]fluoro-PEG-folate, targeting folate receptor β (FRβ), to monitor systemic inflammatory disease in liver and spleen of arthritic rats before and after methotrexate (MTX) treatment. Methods [18F]Fluoro-PEG-folate PET scans (60 min) were acquired in saline- and MTX-treated (1 mg/kg, 4x) arthritic rats, followed by tissue resection and radiotracer distribution analysis. Liver and spleen tissues were stained for ED1/ED2-macrophage markers and FRβ expression. Results [18F]Fluoro-PEG-folate PET and ex vivo tissue distribution studies revealed a significant (p < 0.01) 2-fold lower tracer uptake in both liver and spleen of MTX-treated arthritic rats. Consistently, ED1- and ED2-positive macrophages were significantly (p < 0.01) decreased in liver (4-fold) and spleen (3-fold) of MTX-treated compared with saline-treated rats. Additionally, FRβ-positive macrophages were also significantly reduced in liver (5-fold, p < 0.005) and spleen (3-fold, p < 0.01) of MTX- versus saline-treated rats. Conclusions MTX treatment reduced activated macrophages in liver and spleen, as markers for systemic inflammation in these organs. Macrophage PET imaging with [18F]fluoro-PEG-folate holds promise for detection of systemic inflammation in RA as well as therapy (MTX) response monitoring.

First in man study of [18F]fluoro-PEG-folate PET: a novel macrophage imaging technique to visualize rheumatoid arthritis

“…The [ 18 F]fluoro-PEG-folate biodistribution data were in line with previous preclinical studies; [30][31][32][33]35 . The effective dose of 0.0168 mSv/MBq is lower than similar [ 18 F] tracers such as fludeoxyglucose (FDG), which is currently the main tracer used in clinical practice for imaging of inflammation.…”

“…Recently, [ 18 F]fluoro-PEG-folate (polyethylene glycol folate) has been proposed as a novel candidate folate-based PET tracer 30 . It proved to be an excellent diagnostic tool for both non-invasive visualization of arthritis and monitoring of therapy response to methotrexate and experimental therapies in arthritic rats [31][32][33] .…”

Prophylactic and therapeutic activity of alkaline phosphatase in arthritic rats: single-agent effects of alkaline phosphatase and synergistic effects in combination with methotrexate

“…45,60 This classification may not be that rigid as M2-marcrophages in an arthritic synovial microenvironment with anti-citrullinated protein antibody (ACPA) antibodies and complex IgG autoantibodies were found to produce pro-inflammatory cytokines. 61,62 AP, just like MTX, 63 may thus impact synovial infiltration of polarized inflammatory macrophages.…”

The folate receptor β as a macrophage-mediated imaging and therapeutic target in rheumatoid arthritis

“…In particular, considerable background uptake was seen in periarticular tissue both in a rat model of arthritis [ 48 ] and in RA patients [ 35 ]. To overcome these limitations, a second generation of TSPO tracers was developed, with [ 11 C]DPA713 and [ 18 F]DPA714 [ 50 , 51 ] having been evaluated in preclinical RA models [ 42 , 59 ]. Herein, both [ 11 C]DPA713 and [ 18 F]DPA714 were superior to (R) -[ 11 C]PK11195, but this still needs to be confirmed in a clinical setting.…”

“…Uptake of [ 18 F]-fluoro-PEG-folate was significantly higher in arthritic than in non-inflamed control knees, and also arthritic knee to bone and arthritic knee to blood ratios were higher for [ 18 F]-fluoro-PEG-folate than (R) -[ 11 C]PK11195 [ 48 ]. In addition, using [ 18 F]-fluoro-PEG-folate PET, it was possible to monitor therapeutic effects of MTX in arthritic rats [ 49 ] and to monitor systemic inflammatory effects in an arthritic rat model [ 50 ]. Based on these encouraging preclinical results, [ 18 F]-fluoro-PEG-folate was taken to a clinical setting in which this tracer could readily visualize arthritic joints in RA patients [ 130 ].…”