Simon Vermeire

The effect of medetomidine on the regional cerebral blood flow in dogs measured using Technetium-99m-Ethyl Cysteinate Dimer SPECT

Sedatives and anaesthetics are known to cause changes in the regional cerebral blood flow. In dogs intramuscular sedation with medetomidine, a potent sedative frequently used in veterinary medicine, is sometimes indicated prior to intravenous injection of (99m)Technetium-Ethyl Cysteinate Dimer ((99m)Tc-ECD) in brain perfusion studies using Single Photon Emission Computed Tomography (SPECT). Based on the knowledge of the distribution of alpha(2)-receptors in the brain, we hypothesized altered regional brain perfusion in dogs receiving medetomidine prior to (99m)Tc-ECD. Two conditions were compared in 10 dogs; tracer injection before and after intramuscular sedation with medetomidine. In our study, medetomidine caused a significantly higher tracer uptake in all brain regions. Semi-quantification of brain perfusion rendered a lower perfusion index in the subcortical region and an imbalance between left and right cortical perfusion induced by medetomidine. This study shows that caution is needed when quantifying the brain perfusion indices under medetomidine sedation.

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Alterations of regional brain activity in the prefrontal cortex and in limbic areas have been reported in humans with anxiety disorders. This animal study reports the results of brain perfusion imaging with single photon emission computed tomography (SPECT) in dogs with anxiety disorders. Based on the human literature, we hypothesized altered prefrontal and higher temporal brain perfusion. SPECT acquisitions were performed using the 99mTc-labelled tracer ethyl cysteinate dimer (ECD). Eighteen dogs with pathological anxiety were compared with 18 normally behaving reference dogs. We found, in the group of dogs with anxiety disorders, lower perfusion in the left frontal cortex (p = 0.003), in the subcortical region (p = 0.007) and increased perfusion in the right (p = 0.05) temporal cortex. Taken together, our rCBF findings are suggestive for a dysfunction of the prefrontal cortex and the limbic system in canine anxiety disorders.

Recognition of anatomical predilection sites in canine elbow pathology on bone scans using micro-single photon emission tomography.

The limited resolution of planar bone scintigraphy precludes exact anatomical localisation within a joint. Micro-single photon emission tomography (μ-SPECT) has a much higher resolution, and in this study the use of μ-SPECT in the evaluation of the canine elbow joint and fusion with structural imaging data were tested. Twelve elbows of seven normal dogs were included. μ-SPECT was performed with a conventional triple head gamma camera adapted with three multi-pinhole collimators (HiSPECT). Radiographs, computed tomography (CT) and magnetic resonance imaging (MRI) were performed on all elbows and data from CT and MRI were fused to the HiSPECT data using dedicated software. Different important anatomical regions could be recognised on the HiSPECT images. The improved resolution of the HiSPECT system allowed better differentiation of the anatomical areas in the elbow joint. Two case studies were included to demonstrate the potential of this methodology. Fusion software facilitated the use of combined structural and functional information.

Effects of medetomidine and ketamine on the regional cerebral blood flow in cats: A SPECT study

Brain perfusion can be investigated using single photon emission computed tomography (SPECT) and the intravenous injection of (99m)technetium ethyl cysteinate dimer ((99m)Tc-ECD). However, sedation using medetomidine, an α(2)-agonist, or anaesthesia using medetomidine and ketamine, an N-methyl-d-aspartate-(NMDA)-antagonist, may be required for SPECT studies in cats but can affect the regional cerebral blood flow (rCBF). The effects of medetomidine, with or without ketamine, on regional brain perfusion were therefore investigated in six cats under three conditions. Injection of tracer occurred before sedation or anaesthesia (condition A), following intramuscular (IM) sedation with medetomidine (condition M) or after IM anaesthesia with medetomidine and ketamine (condition MK). Medetomidine and medetomidine with ketamine caused a significantly higher total tracer uptake in all brain regions. Semi-quantification of brain perfusion gave lower perfusion indices in several sub-cortical regions in conditions M and MK, compared to A. Left-right differences were observed in the temporal cortex (A), the temporal, parietal cortex and the thalamus (M) and the frontal cortex (MK). A significantly higher perfusion index in the sub-cortical regions, compared to the whole cortex, was only present in condition A. This study showed that caution is needed when quantifying brain perfusion indices when using sedative or anaesthetic agents that may affect rCBF.

99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

Given the importance of angiogenesis for a tumors survival and growth, several therapeutic strategies rely on the selective inhibition of angiogenesis and the destruction of existing tumor vasculature. These strategies raise the need for a noninvasive tool to evaluate tumor vasculature. We describe the radiosynthesis and evaluation of an imaging tracer that specifically binds tumor subendothelial collagen and thereby images tumor vasculature. Methods: 99mTc-tricarbonyl was prepared and labeled with His–collagen-binding adhesion protein 35 (CNA35). After in vitro specificity testing, in vivo biodistribution and dosimetric studies were performed in healthy nude mice via planar imaging. 99mTc-(CO)3 His-CNA35 was evaluated for in vivo imaging of tumor vasculature in a HT29 colorectal carcinoma xenograft. Results: The labeling procedure yielded a compound with 95%–99% radiochemical purity and good in vitro stability. An in vitro binding test confirmed specificity and functionality. 99mTc-(CO)3 His-CNA35 rapidly cleared from the blood and predominantly accumulated in the kidneys and liver. The effective dose for a proposed single injection of 500 MBq of 99mTc-(CO)3 His-CNA35 is 3.70 mSv per organ or 2.01 mSv/g of tissue. Tumors were successfully visualized, and uptake correlated with ex vivo immunohistochemical staining of tumor vasculature. Conclusion: 99mTc-(CO)3 His-CNA35 may be a useful radioligand for the in vivo detection of tumor vasculature through subendothelial collagen binding. A noninvasive method of imaging tumor vasculature that could provide a reliable assessment of tumor vasculature would allow evaluation of the effectiveness of commonly used antiangiogenic therapies and determination of their optimal dosing and scheduling.

Desirability function combining metabolic stability and functionality of peptides

The evaluation of peptides as potential therapeutic or diagnostic agents requires the consideration of several criteria that are targeted around two axes: functionality and metabolic stability. Most often, a compromise has to be made between these mutually opposing characteristics.

Evaluation of serotonin-2A receptor occupancy with 123I-5-I-R91150 and single-photon emission tomography before and after low-dose pipamperone administration in the canine brain.

PurposeTo conduct a cost-efficient pilot study on the effect of low-dose pipamperone on the serotonin-2A receptor binding in a large animal model with conventional single-photon emission tomography modalities. MethodsThree healthy drug-naive female Beagle dogs were scanned before and after administration of a single-dose pipamperone of 5 and 10 mg. Acquisition was performed under general anesthesia 90 min after injection of the specific radioligand 123I-5-I-R91150 with a triple head &ggr;-camera (Triad, Trionix). Binding index and receptor occupancy were calculated on the emission data after image fusion with the emission data from the individual 99mTc-ethyl cysteinate dimer perfusion scans to optimize frontal cortex delineation. ResultsA dose-dependent reduction of the binding index was observed after single low-dose pipamperone, suggestive for competition of this cold compound with the radioligand for the 5-HT2A receptor. The calculated mean-binding serotonin-2A binding index in the frontal cortex was 1.47 before treatment and reduced to 1.28 after one dose of pipamperone 5 mg and to 1.08 after one dose of pipamperone 10 mg. The calculated occupancy was 40.4% after one dose of 5 mg pipamperone and 83% after one dose of 10 mg pipamperone. ConclusionThis experiment supports the hypothesis that pipamperone, even in the low-dose range, significantly blocks serotonin-2A receptors. This study also demonstrates the value of the canine model to investigate the effects of drugs on neurotransmitter systems. Repeated nuclear imaging brain scanning experiments with different paradigms and medication doses are possible with conventional imaging equipment in a well-accepted laboratory species.

High-resolution micro-SPECT to evaluate the regional brain perfusion in the adult Beagle dog

Conventional Single Photon Emission Computed Tomography (SPECT) precludes a detailed evaluation of the subcortical region. Micro-SPECT (μ-SPECT) has a higher resolution, but has not been used to evaluate the dogs brain until now. In this study, μ-SPECT of the brain was evaluated in 10 Beagle dogs. Magnetic Resonance Imaging (MRI) of the brain was used to draw a new region map containing 19 volumes of interest (VOIs). Semi-quantitative analysis of the μ-SPECT data was performed and the regional cerebral perfusion was represented by the perfusion indices (PIs). The highest perfusion was found in the parietal cortex and the lowest in the piriform cortex. An asymmetry toward the left hemisphere in general and a regional asymmetry in the frontal, temporal and parietal cortex were found. This study shows that functional imaging of the canine brain is possible using μ-SPECT and it describes the normal regional brain perfusion in the adult Beagle dog.

Primary and concomitant flexor enthesopathy of the canine elbow

OBJECTIVES To report the characteristics of two types of flexor enthesopathy, primary and concomitant, based on different diagnostic techniques. MATERIALS AND METHODS Over a period of three years a prospective study was performed on dogs admitted for the complaint of elbow lameness. Based on the radiographic findings a selection of dogs underwent a complete series of different imaging modalities. With each technique, pathology of the medial epicondyle and the presence of other elbow disorders were recorded. All joints with signs of flexor pathology apparent with at least three techniques were selected. A distinction was made between primary and concomitant flexor enthesopathy based on the absence or presence of other elbow disorders. RESULTS Primary flexor enthesopathy was diagnosed in 23 joints and concomitant flexor enthesopathy in 20 joints. In 43% of the joints with primary and in 75% of the joints with concomitant flexor enthesopathy, pathology at the medial epicondyle was demonstrated by all techniques. All joints with concomitant flexor enthesopathy had a diagnosis of medial coronoid disease, osteochondritis dissecans, or both. CLINICAL SIGNIFICANCE Pathology at the medial epicondyle is a sign of flexor enthesopathy. It may be present as the only sign in a joint with primary flexor enthesopathy or concomitant with other elbow pathology. In both groups flexor lesions can be demonstrated with different imaging techniques. The distinction between the primary and concomitant form is based on the presence or absence of other elbow pathology, mainly medial coronoid disease. Recognizing both types is important for a correct treatment decision.

5-HT2A Receptors in the Feline Brain: 123I-5-I-R91150 Kinetics and the Influence of Ketamine Measured with Micro-SPECT

Subanesthetic doses of ketamine can be used as a rapid-acting antidepressant in patients with treatment-resistant depression. Therefore, the brain kinetics of 123I-5-I-R91150 (4-amino-N-[1-[3-(4-fluorophenyl)propyl]-4-methylpiperidin-4-yl]-5-iodo-2-methoxybenzamide) and the influence of ketamine on the postsynaptic serotonin-2A receptor (5-hydroxytryptamine-2A, or 5-HT2A) status were investigated in cats using micro-SPECT. Methods: This study was conducted on 6 cats using the radioligand 123I-5-I-R91150, a 5-HT2A receptor antagonist, as the imaging probe. Anesthesia was induced and maintained with a continuous-rate infusion of propofol (8.4 ± 1.2 mg kg−1 followed by 0.22 mg kg−1 min−1) 75 min after tracer administration, and acquisition of the first image began 15 min after induction of anesthesia. After this first acquisition, propofol (0.22 mg kg−1 min−1) was combined with ketamine (5 mg kg−1 followed by 0.023 mg kg−1 min−1), and the second acquisition began 15 min later. Semiquantification, with the cerebellum as a reference region, was performed to calculate the 5-HT2A receptor binding indices (parameter for available receptor density) in the frontal and temporal cortices. The binding indices were analyzed with Wilcoxon signed ranks statistics. Results: The addition of ketamine to the propofol continuous-rate infusion resulted in decreased binding indices in the right frontal cortex (1.25 ± 0.22 vs. 1.45 ± 0.16; P = 0.028), left frontal cortex (1.34 ± 0.15 vs. 1.49 ± 0.10; P = 0.028), right temporal cortex (1.30 ± 0.17 vs. 1.45 ± 0.09; P = 0.046), and left temporal cortex (1.41 ± 0.20 vs. 1.52 ± 0.20; P = 0.046). Conclusion: This study showed that cats can be used as an animal model for studying alterations of the 5-HT2A receptor status with 123I-5-I-R91150 micro-SPECT. Furthermore, an interaction between ketamine and the 5-HT2A receptors resulting in decreased binding of 123I-5-I-R91150 in the frontal and temporal cortices was demonstrated. Whether the decreased radioligand binding resulted from a direct competition between ketamine and 123I-5-I-R91150 or from a decreased affinity of the 5-HT2A receptor caused by ketamine remains to be elucidated.