In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG-folate and positron emission tomography

Arthritis Res Ther. 2017 May 31;19(1):114. doi: 10.1186/s13075-017-1325-x.


Background: Folate 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.

Methods: Arthritic 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.

Results: PET 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.

Conclusion: This 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.

Keywords: Folate receptor β; Macrophages; Methotrexate; Rheumatoid arthritis; [18F]fluoro-PEG-folate.

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Experimental / diagnostic imaging*
  • Arthritis, Experimental / drug therapy
  • Arthritis, Rheumatoid / drug therapy
  • Fluorine Radioisotopes
  • Folic Acid / analogs & derivatives
  • Male
  • Methotrexate / pharmacology*
  • Polyethylene Glycols
  • Positron-Emission Tomography / methods*
  • Rats
  • Rats, Wistar


  • Antirheumatic Agents
  • Fluorine Radioisotopes
  • poly(ethylene glycol)-folate
  • Polyethylene Glycols
  • Folic Acid
  • Methotrexate