Nuclear Medicine Imaging Tracers for Neurology

Tracers to investigate neurological disorders with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) have found many applications. Several molecular targets can be studied in the human brain in vivo, both in health and disease. Initially, most attention was given to tracers for translocator protein (TSPO), deposition of beta-amyloid, and the dopaminergic system. Many clinical studies have been published with application of a variety of tracers for these targets. During the past few years, more tracers have reached the stage of human studies such as imaging agents for tau protein, P2X7 receptor, SV2A receptor, and the cholinergic system. Other targets of interest that have been studied in man to a lesser extent are N-methyl-d-aspartic acid (NMDA), serotonergic, adenosine, gamma-aminobutyric acid (GABA), sigma, opioid, and metabotropic glutamate subtype 5 (mGlu5) receptors. In addition, several transporter systems have received a great deal of attention. Many tracers for new molecular targets are under development and may open new horizons in the future. Most PET tracers for the brain were initially labeled with 11C but were later replaced by 18F-labeled analogs, since this radionuclide enables longer scanning protocols, dissemination to other hospitals, and commercialization. This initial chapter will highlight PET tracers that have already reached the state of human application.</p

Pentylenetetrazol-induced seizures in immature rats provoke long-term changes in adult hippocampal cholinergic excitability

Purpose: We previously demonstrated that the anticholinesterase eserine provokes interictal-like discharges in the CA3 area of hippocampal slices from rats in which generalized seizures had been induced by pentylenetetrazol (PTZ) when immature. In this study, we investigated several factors as the possible mechanism for this effect, including age at convulsions. Methods: Rats were injected with PTZ on postnatal day (P) 18-20 or >P60, and neuronal activity was recorded intra- and extracellularly from CA3 5-10 or >40 days later. In additional experiments, convulsions were triggered by kainate or were blocked by pentobarbital. Hippocampal (a) acetylcholine (ACh) innervation density was measured by immunocytochemistry, and ACh and gamma-aminobutyric acid (GABA) contents were determined by high-performance liquid chromatography (HPLC)-electrospray ionization. Results: The excitatory effect of eserine was the most consistent in slices from rats PTZ-treated when immature and after the long interval, whereas the reverse was true in rats treated as adults. This effect was dependent on the occurrence of a seizure and was less prevalent when the seizure had been provoked by kainate. Adult animals PTZ-treated at P20 did not differ from control in (a) poly- or monosynaptic GABA(A) and GABA(B) CA3 inhibitory postsynaptic potentials (IPSPs); (b) density of ACh innervation; or (c) tissue content of ACh and GABA. Conclusions: A PTZ-induced generalized seizure in immature rat provokes endogenous ACh-induced interictal-like discharges in adult hippocampal CA3. This effect is only transiently observed if the seizure was induced in adult. It does not appear to be related to a change in GABAergic inhibition, in density of ACh innervation, or in ACh or GABA content.Epilepsi

MicroPET imaging of 5-HT1A receptors in rat brain: a test-retest [18F]MPPF study

International audiencePurposeEarlier studies have shown that positron emission tomography (PET) imaging with the radioligand [18F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine1A (5-HT1A) receptors in different regions of animal and human brain, including that of 5-HT1A autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems). MethodsScans from isoflurane-anaesthetised rats (n = 18, including six test-retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model. ResultsValues of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test-retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei. ConclusionsMicroPET brain imaging of 5-HT1A receptors with [18F]MPPF thus represents a promising avenue for investigating 5-HT1A receptor function in rat

MPTP animal model of Parkinsonism: dopamine cell death or only tyrosine hydroxylase impairment? - A study using PET imaging, autoradiography and immunohistochemistry in the cat.

International audienceAIMS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of Parkinson's disease in laboratory animals. It is believed to cause a selective destruction of substantia nigra dopamine neurons, mainly based on a large reduction of tyrosine hydroxylase (TH), the catecholamine's synthesizing enzyme. Unlike Parkinson's disease in humans, however, all animal models are able to recover more or less rapidly from the MPTP induced Parkinsonian syndrome. This raises the question as whether MPTP causes a cell death with a decrease in dopamine transporter or a simple impairment of TH. METHODS: To respond to this question, we quantified in a cat model of Parkinson's disease (MPTP 5 mg/kg i.p. during 5 days) the dopamine transporter using positron emission tomography (PET) imaging and autoradiography of [(11) C]PE2I and compared the data with the TH-immunoreactivity. RESULTS: We found no changes in [(11) C]PE2I PET binding either 5 or 26 days after MPTP treatment when compared to baseline levels. Similarly, there were no significant changes in [(11) C]PE2I autoradiographic binding in the cat brain one week after MPTP treatment. In sharp contrast, MPTP treated cats exhibited severe Parkinson-like motor syndrome during the acute period with a marked decrease in TH-immunoreactivity in the striatum. CONCLUSION: These data suggest that MPTP toxicity impairs efficiently TH and that such an effect is not necessarily accompanied by significant reduction of dopamine transporter seen with in vitro or in vivo [(11) C]PE2I binding

In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging

International audienceIn neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT1A receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT1A-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT1A radiotracer, [18F]MPPF. Drug occupancy was evaluated after injection at  50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT1A receptor occupancy was found to be dose-dependent for both agonists, but differed in magnitude and spatial distribution at equal doses with distinct BOLD patterns. Functional connectivity, as measured by BOLD signal temporal correlations between regions, was also differently modified by NLX-112 or NLX-101. Voxel-based correlation analyses between PET and fMRI suggested that NLX-112 stimulates both 5-HT1A autoreceptors and post-synaptic receptors, whereas NLX-101 preferentially stimulates post-synaptic cortical receptors. In cingulate cortex, the agonists induced opposite BOLD signal changes in response to receptor occupancy. These data constitute the first simultaneous exploration of 5-HT1A occupancy and its consequences in terms of brain activation, and demonstrates differential signalling by two 5-HT1A-biased agonists. Combined PET/fMRI represents a powerful tool in neuropharmacology, and opens new ways to address the concept of biased agonism by translational approaches