Anaesthesia for positron emission tomography scanning of animal brains

Alstrup, Aage Kristian Olsen; Smith, Donald F.

doi:10.1258/la.2012.011173

Cited by 77 publications

(67 citation statements)

References 87 publications

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“…The choice of anesthesia is important in small-animal PET experiments because it can have a considerable impact on receptor availability, tracer uptake, cerebral blood flow, cerebral blood volume, and brain metabolism (18,19). To date, little has been known on whether PET findings using the serotonin reuptake inhibitor 11 C-DASB are affected by different types of anesthesia.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

et al. 2015

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Serotonin, or 5-hydroxytryptamine (5-HT), plays a key role in the central nervous system and is involved in many essential neurologic processes such as mood, social behavior, and sleep. The serotonin transporter ligand 11 C-3-amino-4(2-dimethylaminomethyl-phenylsufanyl)-benzonitrile ( 11 C-DASB) has been used to determine nondisplaceable binding potential (BP ND ), which is defined as the quotient of the available receptor density (B avail ) and the apparent equilibrium dissociation rate constant (1/appK D ) under in vivo conditions. Because of the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of 11 C-DASB to rats and mice. Here, we assessed the feasibility of using 11 C-DASB for quantification of serotonin transporter (SERT) density and affinity in vivo in rats and mice. Methods: Rats and mice underwent 4 PET scans with increasing doses of the unlabeled ligand to calculate B avail and appK D using the multiple-ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. BP ND was calculated using the simplified reference tissue model, and the results for different reference regions were compared. Results: Displaceable binding of 11 C-DASB was found in all brain regions of both rats and mice, with the highest binding being in the thalamus and the lowest in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which in mice was spatially indistinguishable from cerebellar white matter. Use of the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test-retest reproducibility in the thalamus was more than 90% in both mice and rats. In rats, B avail , appK D , and ED 50 were 3.9 ± 0.4 pmol/mL, 2.2 ± 0.4 nM, and 12.0 ± 2.6 nmol/kg, respectively, whereas analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass. Conclusion: Our data showed that in rats, 11 C-DASB can be used to quantify SERT density with good reproducibility. BP ND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region. Ser otonergic neurons accumulate mainly in the brainstem and form the raphe nuclei (1). Although the raphe nuclei consist of only a few neurons, these nuclei innervate nearly all brain regions (1). Under normal physiologic conditions, the membranebound, sodium-chloride-dependent SERT (serotonin transporter, or 5-hydroxytryptamine [5-HT] transporter) is responsible for specific reuptake of released serotonin by cells (2). This transporter is located on the soma, dendritic collaterals, and entire axon of serotonergic neurons (3).One of the most promising noninvasive imaging approaches for visualizing the distribution of SERT is the SERT mark...

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Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

et al. 2015

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“…Serotonin, like other biologic molecules, is involved in multiple physiologic systems of relevance during anesthesia, and evidence has shown that anesthesia can play a potential role in radiotracer uptake and binding (28,29). Thus, it is possible that the use of anesthesia could have a secondary effect on 18 F-MNI698 uptake and binding.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

et al. 2014

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Serotonin 4 receptors (5-hydroxytryptamine receptor 4 [5HT4R]) hold promise as a novel therapeutic approach to multiple brain disorders, including Alzheimer and Huntington disease. In vivo imaging of these receptors with selective 5HT4R radiotracers and PET would be valuable to investigate alterations in 5HT4R in different brain disorders and to assist drug discovery. In this study, 18 F-MNI698 was evaluated as a potential PET radiotracer for imaging of 5HT4R in the brain. Methods: Eighteen PET studies were performed in 3 adult rhesus monkeys. The radiotracer was administered as a bolus intravenous injection or bolus plus constant infusion (time that would be required to inject the bolus at the infusion rate 5 60 min), and arterial blood was collected for data quantification. Kinetic models were used to estimate distribution volumes and binding potentials, for which the cerebellum was used as a reference region. 18 F-MNI698 test-retest variability and upper mass dose limits were determined. Preblocking studies using several doses of SB204070, a selective 5HT4R antagonist, were performed. Results: 18 F-MNI698 avidly entered the monkey brain (peak percentage injected dose of ∼6.6%), and its brain distribution was consistent with known 5HT4R densities. At 120 min after bolus injection and after the start of radiotracer infusion, only less than 5% and approximately 10% parent compound was present in blood, respectively. Measured binding potentials were underestimated by 22%-36% when noninvasive methods were used for data quantification in comparison with invasive methods. A good agreement was found between test-retest measurements. The radiotracer upper mass dose limit (,5% occupancy) was determined to be 13.1 μg per 70 kg of body weight. SB204070 blocked the radiotracer binding in a dose-dependent manner. Conclusion: Data indicate that 18 F-MNI698 is a promising PET radiotracer for imaging of 5HT4R in the brain, and human studies are warranted based on these study results.

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“…On arrival to the PET Center, pigs were anesthetized by intramuscular injection of midazolam, followed by intubation and isoflurane anesthesia (15,16). Catheters were inserted in the urinary bladder, femoral vein, and femoral artery.…”

Section: Pet Imagingmentioning

confidence: 99%

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

et al. 2014

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Neuropeptide Y2 (NPY2) receptors are implicated in diverse brain disorders, but no suitable PET radiotracers are currently available for studying NPY2 receptors in the living brain. We developed a novel positron-emitting radioligand based on the NPY2 receptor antagonist JNJ-31020028 (N-(4-(4-[2-(diethylamino)-2-oxo-1-phenylethyl] piperazin-1-yl)-3-fluorophenyl)-2-pyridin-3-ylbenzamide) and used the radiotracer for PET brain imaging in pigs. Methods: In vitro receptor autoradiography studies were performed to establish the anatomic distribution of NPY2 receptors in the pig brain. In vivo, baseline 90-min PET recordings of N-11 C-methyl-JNJ-31020028 were conducted in anesthetized Yorkshire x Landrace pigs, concurrent with arterial blood sampling. Postchallenge scans were conducted after injection of unlabeled JNJ-31020028 as a pharmacologic intervention. Cyclosporine A was used to enhance levels of the PET radiotracer in the brain. The PET images were manually coregistered to a MR imaging atlas of the pig brain. Maps of the N-11 C-methyl-JNJ-31020028 volume of distribution in the brain were prepared, and regional binding potentials of NPY2 receptors toward the radio-ligand were calculated using the simplified reference tissue method. Results: In autoradiography studies, N-11 C-methyl-JNJ-31020028 receptor binding sites were observed primarily in the hippocampus and were inhibited by unlabeled JNJ-31020028. In PET studies, N-11 C-methyl-JNJ-31020028 was metabolized slowly in the bloodstream , with 25% of the 11 C-labeled parent compound remaining 30 min after injection. PET imaging showed baseline binding potentials of 0.64 ± 0.07 in the thalamus, 0.55 ± 0.02 in the caudate, and 0.49 ± 0.03 in the hippocampus. Graphical reference region analyses demonstrated that N-11 C-methyl-JNJ-31020028 binding was reversible; infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in the hippocampus, thalamus, caudate nucleus, and cerebellum but not in the corpus callosum, which served as reference region for nonspecific binding. Conclusion: N-11 C-methyl-JNJ-31020028 has several suitable properties for PET neuroimaging of NPY2 receptors. First, it is metabolized slowly in the bloodstream of pigs. Second, using cyclosporine, the target-to-background ratio of N-11 C-methyl-JNJ-31020028 is sufficient for estimating pharmacokinetic parameters. Third, N-11 C-methyl-JNJ-31020028 binds reversibly and competitively to cerebral sites known to contain relatively high numbers of NPY2 receptors, such as the hippocampus, thalamus, caudate nucleus, and cerebellum. Fourth, white matter such as corpus callosum, known to contain negligible numbers of NPY2 receptors, can serve as a reference region for estimating binding potentials in brain regions. To our knowledge, there is no other radioligand with these favorable properties and with this specificity for NPY2 receptors, which makes N-11 C-methyl-JNJ-31020028 the first candidate radioligand for PET investigations of NPY2 receptors in the living brain.

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Anaesthesia for positron emission tomography scanning of animal brains

Cited by 77 publications

References 87 publications

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

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Anaesthesia for positron emission tomography scanning of animal brains

Cited by 77 publications

References 87 publications

In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of 18F-MNI698: An 18F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-11C-Methyl-JNJ-31020028 in Pigs

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Product

Resources

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In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs