Molecular imaging constitutes a promising technique for the early detection of rheumatoid arthritis (RA). Macrophages and hypoxia play significant roles in inflamed synovium. In the present study, we evaluated the efficacy of radiopharmaceuticals that target macrophage mannose receptors (Tc-labeled mannosylated dextran or Tc(CO)-DCM20) and hypoxia (copper(II) diacetyl-di(N-methylthiosemicarbazone) or Cu-ATSM) for the early detection of RA in collagen-induced arthritis (CIA) mice models. CIA model was developed in DBA/1 mice, and the clinical score for arthritis was visually assessed on a regular basis. Two biodistribution studies were performed in a paired-labeled format using 2-deoxy-2-F-fluoro-D-glucose (F-FDG) as a reference: (1) Tc(CO)-DCM20 with F-FDG and (2) Cu-ATSM with F-FDG. The accumulation levels of Tc(CO)-DCM20 and Cu-ATSM in forepaws, hindpaws, and knee joints of CIA mice were significantly higher than that of control mice. In contrast, F-FDG uptake in hindpaws and knee joints showed no significant difference between CIA and control mice. The radioactivity levels of Tc(CO)-DCM20 and Cu-ATSM were significantly correlated with the clinical scores for the paws. These resu