Dataset Information

Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

ABSTRACT: BACKGROUND:[68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. METHODS:Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal's non-infected left hind limb was used as a control. RESULTS:Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. CONCLUSION:The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.

SUBMITTER: Jodal L

PROVIDER: S-EPMC6891593 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Kinetic Modelling of [<sup>68</sup>Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

Jødal Lars L Roivainen Anne A Oikonen Vesa V Jalkanen Sirpa S Hansen Søren B SB Afzelius Pia P Alstrup Aage K O AKO Nielsen Ole L OL Jensen Svend B SB

Molecules (Basel, Switzerland) 20191113 22

<h4>Background</h4>[<sup>68</sup>Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [<sup>68</sup>Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs.<h4>Methods</h4>Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynami ...[more]

PMID: 31766140

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Project description:Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results: 68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.

Project description:PurposeInflammatory bowel disease (IBD) can be imaged with positron emission tomography (PET), but existing PET radiopharmaceuticals have limited diagnostic accuracy. Vascular adhesion protein-1 (VAP-1) is an endothelial cell surface molecule that controls leukocyte extravasation into sites of inflammation. However, the role of inflammation-induced VAP-1 expression in IBD is still unclear. Therefore, this study investigated the utility of VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 positron emission tomography/computed tomography (PET/CT) for assessing inflammation in two mouse models of IBD.ProceduresStudies were performed using K8-/- mice that develop a chronic colitis-phenotype and C57Bl/6NCrl mice with acute intestinal inflammation chemically-induced using 2.5% dextran sodium sulfate (DSS) in drinking water. In both diseased and control mice, uptake of the VAP-1-targeting peptide [68Ga]Ga-DOTA-Siglec-9 was assessed in intestinal regions of interest using in vivo PET/CT, after which ex vivo gamma counting, digital autoradiography, and histopathological analyses were performed. Immunofluorescence staining was performed to determine VAP-1-expression in the intestine, including in samples from patients with ulcerative colitis.ResultsIntestinal inflammation could be visualized by [68Ga]Ga-DOTA-Siglec-9 PET/CT in two murine models of IBD. In both models, the in vivo PET/CT and ex vivo studies of [68Ga]Ga-DOTA-Siglec-9 uptake were significantly higher than in control mice. The in vivo uptake was increased on average 1.4-fold in the DSS model and 2.0-fold in the K8-/- model. Immunofluorescence staining revealed strong expression of VAP-1 in the inflamed intestines of both mice and patients.ConclusionsThis study suggests that the VAP-1-targeting [68Ga]Ga-DOTA-Siglec-9 PET tracer is a promising tool for non-invasive imaging of intestinal inflammation. Future studies in patients with IBD and evaluation of the potential value of [68Ga]Ga-DOTA-Siglec-9 in diagnosis and monitoring of the disease are warranted.

Project description:BACKGROUND:Lanreotide is a long-acting somatostatin analogue with proven antitumour effects against well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumours (GEP-NETs). However, there are no globally established prognostic factors associated with the efficacy of lanreotide as a treatment for GEP-NETs. We investigated the prognostic value of [68Ga]Ga-DOTA-TOC positron emission tomography (PET)/computed tomography (CT) somatostatin receptor imaging for patients with WD GEP-NETs treated with lanreotide. METHODS:In this retrospective study, we included 31 patients with unresectable or metastatic WD GEP-NETs who received lanreotide and underwent [68Ga]Ga-DOTA-TOC PET/CT before receiving lanreotide. We captured the following clinicopathological variables: Eastern Cooperative Oncology Group (ECOG) performance status, primary tumour site, NET World Health Organization grade, existence of carcinoid symptoms, previous surgery, previous chemotherapy, and hepatic tumour volume assessed by CT or magnetic resonance imaging (MRI). We also assessed the following [68Ga]Ga-DOTA-TOC PET/CT variables: Krenning score, tumour-to-liver ratio (TLR), maximum standardized uptake value (SUVmax), whole tumour volume (WTV), and total receptor expression (TRE, WTV multiplied by SUVmean). The associations between these markers and progression-free survival (PFS) with lanreotide were analysed. RESULTS:The mean age was 55.1 ± 15.5?years (range 16.0-81.0). The most common primary tumour site was the pancreas, followed by the stomach, and rectum. The median PFS interval with lanreotide was 14.4?months (range 1.3-34.9), with identified disease progression in 20 patients (64.5%). Among the [68Ga]Ga-DOTA-TOC PET/CT variables, TLR (< 8.1 vs. ? 8.1; p = 0.013), SUVmax (< 42.9 vs. ? 42.9; p = 0.037), and WTV (? 58.9?cm3 vs. < 58.9?cm3; p = 0.030) were significantly associated with PFS in the univariate analyses, but only TLR (hazard ratio 3.182 [95% CI 1.189-8.514], p = 0.021) remained an independent factor for PFS in the multivariate analysis. CONCLUSIONS:Low TLR, determined via [68Ga]Ga-DOTA-TOC PET/CT, can be a factor of worse prognosis in patients with advanced WD GEP-NETs treated with lanreotide.

Dataset Information

Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

Publications

Kinetic Modelling of [<sup>68</sup>Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

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