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Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

ABSTRACT: BACKGROUND:Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics. OBJECTIVE:A clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthritis in RA patients. METHODS:RA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of [18F]DPA-714, [11C]DPA-713 and/or (R)-[11C]PK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison. RESULTS:Clinically active arthritis was present in 110 hand joints (2-17 pp). Arthritic joints were visualized with both [11C]DPA-713 and [18F]DPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for [11C]DPA-713 than for [18F]DPA-714, the latter being not significantly different from (R)-[11C]PK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-[11C]PK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for [11C]DPA-713. CONCLUSIONS:[11C]DPA-713 and [18F]DPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for [11C]DPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA.

SUBMITTER: Bruijnen STG

PROVIDER: S-EPMC6760780 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

Bruijnen S T G STG Verweij N J F NJF Gent Y Y J YYJ Huisman M C MC Windhorst A D AD Kassiou M M van de Ven P M PM Lammertsma A A AA Hoekstra O S OS Voskuyl A E AE van der Laken C J CJ

PloS one 20190925 9

<h4>Background</h4>Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics.<h4>Objective</h4>A clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthriti ...[more]

PMID: 31553762

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Project description:IntroductionEarly diagnosis of and subsequent monitoring of therapy for rheumatoid arthritis (RA) could benefit from detection of (sub)clinical synovitis. Imaging of (sub)clinical arthritis by targeting the translocator protein (TSPO) on activated macrophages is feasible using (R)-[¹¹C] PK11195-based positron emission tomography (PET), but clinical applications are limited by background uptake in peri-articular bone/bone marrow. The purpose of the present study was to evaluate two other TSPO ligands with potentially lower background uptake in neurological studies, [¹¹C]DPA-713 and [¹?F]DPA-714, in a rat model of arthritis.MethodsTSPO binding of DPA-713, DPA-714 and PK11195 were assessed by in vitro competition studies with [³H]DPA-713 using human macrophage THP-1 cells and CD14? monocytes from healthy volunteers. In vivo studies were performed in rats with methylated bovine serum albumin-induced knee arthritis. Immunohistochemistry with anti-TSPO antibody was performed on paraffin-embedded sections. Rats were imaged with [¹¹C]DPA-713 or [¹?F]DPA-714 PET, followed by ex vivo tissue distribution studies. Results were compared with those obtained with the tracer (R)-[¹¹C]PK11195, the established ligand for TSPO.ResultsIn THP-1 cells, relative TSPO binding of DPA-713 and DPA-714 were 7-fold and 25-fold higher, respectively, than in PK11195. Comparable results were observed in CD14? monocytes from healthy volunteers. In the arthritis rat model, immunohistochemistry confirmed the presence of TSPO-positive inflammatory cells in the arthritic knee. PET images showed that uptake of [¹¹C]DPA-713 and [¹?F]DPA-714 in arthritic knees was significantly increased compared with contralateral knees and knees of normal rats. Uptake in arthritic knees could be largely blocked by an excess of PK11195. [¹¹C]DPA-713 and [¹?F]DPA-714 provided improved contrast compared with (R)-[¹¹C]PK11195, as was shown by significantly higher arthritic knee-to-bone ratios of [¹¹C]DPA-713 (1.60?±?0.31) and [¹?F]DPA-714 (1.55?±?0.10) compared with (R)-[¹¹C]PK11195 (1.14?±?0.19).Conclusions[¹¹C]DPA-713 and [¹?F]DPA-714 clearly visualized arthritis and exhibited lower (peri-articular) bone/bone marrow uptake than (R)-[¹¹C]PK11195. These features merit further investigation of these tracers for early diagnosis and therapy monitoring of RA in a clinical setting.

Project description:ObjectiveTo determine the prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis (RA).MethodsRA patients (n = 119) without known cardiovascular disease underwent cardiac 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT). Myocardial FDG uptake was assessed visually and measured quantitatively as the standardized uptake value (SUV). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUVs. A subset of RA patients who had to escalate their disease-modifying antirheumatic drug (DMARD) therapy (n = 8) underwent a second FDG PET-CT scan after 6 months, to assess treatment-associated changes in myocardial FDG uptake.ResultsVisually assessed FDG uptake was observed in 46 (39%) of the 119 RA patients, and 21 patients (18%) had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean SUV [SUVmean ] ≥3.10 units; defined as 2 SD above the value in a reference group of 27 non-RA subjects). The SUVmean was 31% higher in patients with a Clinical Disease Activity Index (CDAI) score of ≥10 (moderate-to-high disease activity) as compared with those with lower CDAI scores (low disease activity or remission) (P = 0.005), after adjustment for potential confounders. The adjusted SUVmean was 26% lower among those treated with a non-tumor necrosis factor-targeted biologic agent compared with those treated with conventional (nonbiologic) DMARDs (P = 0.029). In the longitudinal substudy, the myocardial SUVmean decreased from 4.50 units to 2.30 units over 6 months, which paralleled the decrease in the mean CDAI from a score of 23 to a score of 12.ConclusionSubclinical myocardial inflammation is frequent in patients with RA, is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA.

Dataset Information

Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

Publications

Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

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