Article

Kepe, V. et al. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 103, 702-707

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2006; 103(3):702-7. DOI: 10.1073/pnas.0510237103
Source: PubMed

ABSTRACT

4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

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Available from: Kooresh Shoghi, Aug 12, 2014
    • "This allows research in animal models, the findings of which can then be applied in human research and clinical studies. Several animal and human studies with these agents have pointed to a role of the 5-HT 1A receptor in depression (Parsey, 2010), epilepsy (Theodore et al., 2012), Alzheimer's disease (Kepe et al., 2006; Truchot et al., 2008), and other brain functions. Important issues in translational research include 1) similarity (homology) of the biomarker (serotonin 5-HT 1A receptor) across different species and 2) the ability of imaging agents (radiopharmaceutical) to withstand molecular, cellular, and physiological differences between species. "
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    ABSTRACT: We have developed 18F-trans-Mefway (18F-Mefway) for PET imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of 18F-Mefway in normal mice, rats, monkeys and healthy human volunteers. Mefway was found to be very selective with subnanomolar affinity for the serotonin 5-HT1A receptor. Affinities of >55 nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 M) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of 18F-Mefway binding. Consistent binding of 18F-Mefway in cortical regions, hippocampus and raphe was observed across all species. 18F-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in the rodents, while monkeys and humans showed a raphe to cerebellum ratio approximately 3. 18F-Mefway appears to be an effective serotonin 5-HT1A receptor imaging agent in all models including humans. 18F-Mefway therefore may be used to quantify serotonin 5-HT1A receptor distribution in brain regions for the study of various CNS disorders.
    No preview · Article · Oct 2015 · The Journal of Comparative Neurology
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    • "The importance of 5-HT is further highlighted by the association between deregulation of serotonergic signalling and pathogenesis of various diseases ranging from psychiatric and neurological disorders, such as depression (Coppen 1967, Artigas et al. 1996) and Alzheimer's disease (AD) (Tohgi et al. 1992, Kepe et al. 2006), to functional and inflammatory disorders of the GI tract, such as irritable bowel syndrome (IBS) (Bearcroft et al. 1998, Coates et al. 2004, Spiller 2007) and inflammatory bowel disease (IBD) (Bishop et al. 1987, El-Salhy et al. 1997, Coates et al. 2004, Khan & Ghia 2010). Here, we review how 5-HT signalling modulates various biological functions, with a particular focus on its contribution in immune responses and inflam- mation. "
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    ABSTRACT: Serotonin or 5- hydoxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS), and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut; as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as “5-HT,” “EC cell,” “immune cells,” and “inflammation” in pubmed. gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2014 · Acta Physiologica
    • "This allows research in animal models, the findings of which can then be applied in human research and clinical studies. Several animal and human studies with these agents have pointed to a role of the 5-HT 1A receptor in depression (Parsey, 2010), epilepsy (Theodore et al., 2012), Alzheimer's disease (Kepe et al., 2006; Truchot et al., 2008), and other brain functions. Important issues in translational research include 1) similarity (homology) of the biomarker (serotonin 5-HT 1A receptor) across different species and 2) the ability of imaging agents (radiopharmaceutical) to withstand molecular, cellular, and physiological differences between species. "
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    ABSTRACT: Objectives: Serotonin 5-HT1A receptors, implicated in CNS disorders, have been studied with 18F-trans-Mefway (18F-Mefway) in rodent and nonhuman primate studies. Following successful completion of rodent and nonhuman primate studies, we report comparative distribution of 18F-Mefway in humans. Methods: Radiosynthesis of 18F-Mefway was carried out as previously reported. Human 18F-Mefway studies were carried out under an FDA approved IND. Both preclinical and clinical studies were carried out after an IV bolus injection of 18F-Mefway (~0.5 mCi for rat, 2-3 mCi for monkeys, 5 mCi for humans) with specific activity >2Ci/µmol. Isoflurane anesthesia (1.5-3%) was used for rodents and monkeys. Rodent, nonhuman primate and human studies were performed on an Inveon MicroPET/CT, MicroPET P4, and Siemen’s HR+ scanner, respectively. Using ASIPro and PMOD, analysis of 18F-Mefway binding to 5-HT1A receptor-rich regions was performed. Results: Across various species rapid brain uptake of 18F-Mefway was observed in all brain regions. Cerebellum (CB) was used as a reference region in all studies across all species due to a lack of receptor specific binding. Distribution of 18F-Mefway in human brain regions was consistent with the known concentration of 5-HT1A receptors: mesial temporal cortex/ hippocampus (MTC/ HP)> insula (IN) > cingulate gyrus (CG) = dorsal raphe (DR). Human brain regions to cerebellum maximal ratios were found to be MTC/CB=7; IN/CB=5; CG/CB=3.8; DR/CB=3.5. 18F-Mefway brain uptake in humans was not hampered from bone uptake in the skull. Conclusions: Ongoing PET studies in all models including humans have indicated 18F-Mefway to be efficacious as a serotonin 5-HT1A receptor imaging agent. 18F-Mefway therefore may be reliably used to quantify serotonin 5-HT1A receptor distribution in brain regions including small areas such as the DR for the study of various CNS disorders in animal models and human diseases. Research Support: NIH/NIA R33AG030524
    No preview · Conference Paper · Jun 2014
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