One of the most prominent cell populations playing a role in rheumatoid arthritis (RA) is activated fibroblast-like synoviocytes. Among many other proteins, fibroblast-like synoviocytes dominantly express fibroblast activation protein (FAP). Because of the high expression of FAP in arthritic joints, radioimmunoimaging of activated fibroblasts with anti-FAP antibodies might be an attractive noninvasive imaging tool in RA. Methods: SPECT and PET with 111 In-and 89 Zr-labeled anti-FAP antibody 28H1 was performed in mice with CIA. The radioactivity uptake in joints was quantified and correlated with arthritis score. Results: Both 111 In-28H1 and 89 Zr-28H1 showed high uptake in inflamed joints, being 3-fold higher than that of the irrelevant isotype-matched control antibody DP47GS, clearly indicating specific accumulation of 28H1. Uptake of 111 In-28H1 ranged from 2.2 percentage injected dose per gram (%ID/g) in noninflamed joints to 32.1 %ID/g in severely inflamed joints. DP47GS accumulation ranged from 1.6 %ID/g in noninflamed tissue to 12.0 %ID/g in severely inflamed joints. Uptake of 28H1 in inflamed joints correlated with arthritis score (Spearman ρ, 0.69; P , 0.0001) and increased with severity of arthritis. Conclusion: SPECT/CT imaging with the anti-FAP antibody 111 In-28H1 specifically visualized arthritic joints with high resolution, and tracer accumulation correlated with the severity of the inflammation in murine experimental arthritis. Background uptake of the radiolabeled antibody was low, resulting in excellent image quality. 89 Zr-28H1 was less favorable for RA imaging because of an elevated bone uptake of 89 Zr. Future studies will focus on the potential role of 28H1 as a tool to monitor therapy response early on.

Choline kinase is upregulated in prostate cancer, resulting in increased 18 F-fluoromethylcholine uptake. This study used pharmacokinetic modeling to validate the use of simplified methods for quantification of 18 F-fluoromethylcholine uptake in a routine clinical setting. Methods: Forty-minute dynamic PET/CT scans were acquired after injection of 204 ± 9 MBq of 18 F-fluoromethylcholine, from 8 patients with histologically proven metastasized prostate cancer. Plasma input functions were obtained using continuous arterial blood-sampling as well as using image-derived methods. Manual arterial blood samples were used for calibration and correction for plasma-to-blood ratio and metabolites. Time-activity curves were derived from volumes of interest in all visually detectable lymph node metastases. 18 F-fluoromethylcholine kinetics were studied by nonlinear regression fitting of several single-and 2-tissue plasma input models to the time-activity curves. Model selection was based on the Akaike information criterion and measures of robustness. In addition, the performance of several simplified methods, such as standardized uptake value (SUV), was assessed. Results: Best fits were obtained using an irreversible compartment model with blood volume parameter. Parent fractions were 0.12 ± 0.4 after 20 min, necessitating individual metabolite corrections. Correspondence between venous and arterial parent fractions was low as determined by the intraclass correlation coefficient (0.61). Results for image-derived input functions that were obtained from volumes of interest in bloodpool structures distant from tissues of high 18 F-fluoromethylcholine uptake yielded good correlation to those for the blood-sampling input functions (R 2 5 0.83). SUV showed poor correlation to parameters derived from full quantitative kinetic analysis (R 2 , 0.34). In contrast, lesion activity concentration normalized to the integral of the blood activity concentration over time (SUV AUC ) showed good correlation (R 2 5 0.92 for metabolite-corrected plasma; 0.65 for whole-blood activity concentrations). Conclusion: SUV cannot be used to quantify 18 F-fluoromethylcholine uptake. A clinical compromise could be SUV AUC derived from 2 consecutive static PET scans, one centered on a large blood-pool structure during 0-30 min after injection to obtain the blood activity concentrations and the other a whole-body scan at 30 min after injection to obtain lymph node activity concentrations.

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Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis. Methods: Collagen-induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of 99m Tc-labeled succinimidylhydrazinonicotinamide ( 99m Tc-S-HYNIC)-conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of 99m Tc-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores. Results: Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL. 99m Tc-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman r, 0.77; P , 0.0001). Moreover, the uptake of 99m Tc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method. Conclusion: SPECT/CT imaging with 99m Tc-S-HYNIC-28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with 99m Tc-S-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice.

Introduction: Ever since their discovery, liposomes have been radiolabeled to monitor their fate in vivo. Despite extensive preclinical studies, only a limited number of radiolabeled liposomal formulations have been examined in patients. Since they can play a crucial role in patient management, it is of importance to enable translation of radiolabeled liposomes into the clinic.Areas covered: Liposomes have demonstrated substantial advantages as drug delivery systems and can be efficiently radiolabeled. Potentially, radiolabeled drug-loaded liposomes form an elegant theranostic system, which can be tracked in vivo using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. In this review, we discuss important aspects of liposomal research with a focus on the use of radiolabeled liposomes and their potential role in drug delivery and monitoring therapeutic effects. Expert opinion: Radiolabeled drug-loaded liposomes have been poorly investigated in patients and no radiolabeled liposomes have been approved for use in clinical practice. Evaluation of the risks, pharmacokinetics, pharmacodynamics and toxicity is necessary to meet pharmaceutical and commercial requirements. It remains to be demonstrated whether the results found in animal studies translate to humans before radiolabeled liposomes can be implemented into clinical practice. ARTICLE HISTORY