Dose Optimization for Using the Contrast Agent Gadofosveset in Magnetic Resonance Imaging (MRI) of Domestic Pig Brain

Pigs are useful models in stroke research, and Magnetic Resonance Imaging (MRI) is a useful tool for measurements of brain pathophysiology. Perfusion Weighed Imaging (PWI) with standard Gd-based chelates (i.e. gadobutrol) provides crucial information about breakdown of the Blood-Brain-Barrier (BBB) in patients. Gadofosveset is also a Gd-based contrast agent, but with a higher binding to serum albumin. The prolonged plasma-half life of gadofosveset allows the acquisition of steady state angiographies, which may increase the sensitivity for detection of BBB leakage. We hypothesize that the contrast dosage with gadofosveset can be optimized for PWI and subsequent steady-state Magnetic Resonance Angiography (MRA) in pigs. Anesthetized domestic pigs (females; N=6) were MRI scanned four times in one day: they were initially imaged during a standard gadobutrol bolus injection (0.1 mmol/kg). Then they received three successive gadofosveset bolus injections of varying dosages (0.015-0.09 mmol/kg). Based on projection from our data, we suggest that a bolus injection of 0.0916 mmol/kg gadofosveset would yield contrast similar to that of a standard dose of 0.1 mmol/kg gadobutrol in dynamic susceptibility contrast MRI at 3 T. In conclusion, our results demonstrate the feasibility of gadofosveset based PWI in pig brain research. The relaxation and plasma half-life properties allow detailed steady-state MRA angiographies and may prove useful in detecting subtle BBB disruption of significance in stroke models and human patients

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

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

Kinetic Modelling of Infection Tracers [ 18

Introduction. Positron emission tomography (PET) is increasingly applied for infection imaging using [18F]FDG as tracer, but uptake is unspecific. The present study compares the kinetics of [18F]FDG and three other PET tracers with relevance for infection imaging. Methods. A juvenile porcine osteomyelitis model was used. Eleven pigs underwent PET/CT with 60-minute dynamic PET imaging of [18F]FDG, [68Ga]Ga-citrate, [11C]methionine, and/or [11C]donepezil, along with blood sampling. For infectious lesions, kinetic modelling with one- and two-tissue-compartment models was conducted for each tracer. Results. Irreversible uptake was found for [18F]FDG and [68Ga]Ga-citrate; reversible uptake was found for [11C]methionine (two-tissue model) and [11C]donepezil (one-tissue model). The uptake rate for [68Ga]Ga-citrate was slow and diffusion-limited. For the other tracers, the uptake rate was primarily determined by perfusion (flow-limited uptake). Net uptake rate for [18F]FDG and distribution volume for [11C]methionine were significantly higher for infectious lesions than for correspondingly noninfected tissue. For [11C]donepezil in pigs, labelled metabolite products appeared to be important for the analysis. Conclusions. The kinetics of the four studied tracers in infection was characterized. For clinical applications, [18F]FDG remains the first-choice PET tracer. [11C]methionine may have a potential for detecting soft tissue infections. [68Ga]Ga-citrate and [11C]donepezil were not found useful for imaging of osteomyelitis

Blood perfusion in osteomyelitis studied with [O-15] water PET in a juvenile porcine model

Abstract Background Osteomyelitis is a serious disease which can be difficult to treat despite properly instituted antibiotic therapy. This appears to be related at least partly to degraded vascularisation in the osteomyelitic (OM) lesions. Studies of perfusion in OM bones are, however, few and not quantitative. Quantitative assessment of perfusion could aid in the selection of therapy. A non-invasive, quantitative way to study perfusion is dynamic [ 15 O]water positron emission tomography (PET). We aim to demonstrate that the method can be used for measuring perfusion in OM lesions and hypothesize that perfusion will be less elevated in OM lesions than in soft tissue (ST) infection. The study comprised 11 juvenile pigs with haematogenous osteomyelitis induced by injection of Staphylococcus aureus into the right femoral artery 1\ua0week before scanning (in one pig, 2\ua0weeks). The pigs were dynamically PET scanned with [ 15 O]water to quantify blood perfusion. OM lesions ( N \u2009=\u200917) in long bones were studied, using the left limb as reference. ST lesions ( N \u2009=\u20098) were studied similarly. Results Perfusion was quantitatively determined. Perfusion was elevated by a factor 1.5 in OM lesions and by a factor 6 in ST lesions. Conclusions Blood perfusion was successfully determined in pathological subacute OM lesions; average perfusion was increased compared to that in a healthy bone, but as hypothesized, the increase was less than in ST lesions, indicating that the infected bone has less perfusion reserve than the infected soft tissue