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1.
Transl Psychiatry ; 8(1): 264, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504860

RESUMO

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.


Assuntos
Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Dopamina/metabolismo , Adulto , Mapeamento Encefálico , Corpo Estriado/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Tomografia por Emissão de Pósitrons , Racloprida
2.
Psychoneuroendocrinology ; 91: 123-131, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29550675

RESUMO

The µ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the µ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human µ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective µ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known µ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others' happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of µ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that µ-opioids mediate social confidence and reduce sensitivity to threat cues.


Assuntos
Reconhecimento Facial/efeitos dos fármacos , Morfina/farmacologia , Percepção/efeitos dos fármacos , Adulto , Afeto/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Ira/efeitos dos fármacos , Atenção/efeitos dos fármacos , Sinais (Psicologia) , Método Duplo-Cego , Emoções/efeitos dos fármacos , Emoções Manifestas/efeitos dos fármacos , Expressão Facial , Feminino , Felicidade , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/metabolismo
3.
J Nucl Med ; 58(12): 2004-2009, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28572487

RESUMO

The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent 18F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one (18F-FTC-146). Methods: Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to 18F-FTC-146 were reported. High accumulation of 18F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of 18F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade 18F-FTC-146 were successful. Injection of 18F-FTC-146 is safe, and absorbed doses are acceptable. The potential of 18F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.


Assuntos
Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Azepinas/efeitos adversos , Azepinas/síntese química , Benzotiazóis/efeitos adversos , Benzotiazóis/síntese química , Feminino , Voluntários Saudáveis , Humanos , Marcação por Isótopo , Imagem por Ressonância Magnética , Masculino , Imagem Multimodal , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Distribuição Tecidual , Imagem Corporal Total
4.
Mol Imaging Biol ; 19(5): 779-786, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28280965

RESUMO

PURPOSE: Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [18F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [18F]FTC-146. PROCEDURES: [18F]FTC-146 is prepared via a direct [18F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [18F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects. RESULTS: [18F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/µmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [18F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [18F]FTC-146 was observed in cortical bone and muscle. CONCLUSION: A reliable and automated radiosynthesis for providing routine clinical-grade [18F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.


Assuntos
Azepinas/química , Azepinas/síntese química , Benzotiazóis/química , Benzotiazóis/síntese química , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Adulto , Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Feminino , Humanos , Masculino , Distribuição Tecidual
5.
Nucl Med Biol ; 43(8): 478-89, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27236283

RESUMO

INTRODUCTION: The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood-brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [(18)F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these (18)F-labeled compounds in brain of living rats. METHODS: We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for (18)F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo. RESULTS: A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The (18)F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5-15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the (18)F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding in vivo. CONCLUSIONS: The novel small molecule (18)F-fluorinated GnRH-R antagonist compounds show high receptor affinity in vitro, and may prove useful for quantitative autoradiographic studies in vitro. The compounds were permeable to the blood-brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor , Furanos/síntese química , Furanos/metabolismo , Receptores LHRH/antagonistas & inibidores , Animais , Técnicas de Química Sintética , Furanos/farmacocinética , Furanos/farmacologia , Masculino , Permeabilidade , Tomografia por Emissão de Pósitrons , Radioquímica , Ratos , Ratos Sprague-Dawley , Especificidade por Substrato , Distribuição Tecidual
6.
J Med Chem ; 57(12): 5464-9, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24933507

RESUMO

We report the synthesis and biological evaluation of a triplet of 6-O-(18)F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [(18)F]fluoroethyl-diprenorphine, [(18)F]fluoroethyl-buprenorphine, and [(18)F]fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-(18)F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.


Assuntos
Buprenorfina/análogos & derivados , Diprenorfina/análogos & derivados , Morfinanos/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Buprenorfina/síntese química , Buprenorfina/química , Buprenorfina/farmacocinética , Células CHO , Radioisótopos de Carbono , Cricetulus , Diprenorfina/síntese química , Diprenorfina/química , Diprenorfina/farmacocinética , Radioisótopos de Flúor , Humanos , Morfinanos/química , Morfinanos/farmacocinética , Antagonistas de Entorpecentes , Tomografia por Emissão de Pósitrons , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
7.
J Neurosci Methods ; 199(1): 166-72, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21550366

RESUMO

Anatomical standardization (also called spatial normalization) of positron emission tomography (PET) small animal brain images is required to make statistical comparisons across individuals. Frequently, PET images are co-registered to an individual MR or CT image of the same subject in order to transform the functional images to an anatomical space. In the present work, we evaluate the normalization of synthetic PET (synPET) images to a synthetic PET template. To provide absolute error in terms of pixel misregistration, we created a synthetic PET image from the individual MR image through segmentation of the brain into gray and white matter which produced functional and anatomical images in the same space. When comparing spatial normalization of synPET images to a synPET template with the gold standard (MR images to an MR template), a mean translation error of 0.24mm (±0.20) and a maximal mean rotational error of 0.85° (±0.91) were found. Significant decrease in misregistration error was measured when achieving spatial normalization of functional images to a functional template instead of an anatomical template. This accuracy strengthens the use of standardization methods where individual PET images are registered to a customized PET template in order to statistically assess physiological changes in rat brains.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/veterinária , Tomografia por Emissão de Pósitrons/veterinária , Ratos/anatomia & histologia , Animais , Encéfalo/metabolismo , Feminino , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Valores de Referência
8.
Clin Physiol Funct Imaging ; 30(4): 285-93, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20662879

RESUMO

INTRODUCTION: Neuronal events leading to development of long-term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord. METHODS: Spinal LTP was induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve, and the excitability at spinal level was verified by spinal field potential recordings. To study supraspinal changes in opioid neurotransmission following the same HFS conditioning, we used small animal positron emission tomography (PET) and [(11)C]Phenethyl-Orvinol ([(11)C]PEO). All rats included in the PET study were scanned at baseline and 150 min after HFS, and specific binding was calculated with a reference tissue model. RESULTS: A clear C-fibre LTP, i.e. increased C-fibre response and reduced C-fibre threshold, was observed 150 min after HFS conditioning (t-test, P<0.05, n = 6). Moreover, increased OR binding, relative to baseline, was observed after the same type of HFS conditioning ipsilaterally in the amygdala, hippocampus, somatosensory cortex and superior colliculus, and bilaterally in the nucleus accumbens, caudate putamen and hypothalamus (paired t-test, HFS>baseline, P<0.05, n = 8). CONCLUSIONS: HFS conditioning of the sciatic nerve resulted in both spinal LTP and functional changes in supraspinal opioidergic signalling. Our findings suggest that induction of spinal LTP may be associated with reduced opioid neurotransmission in brain regions involved in pain modulation and affective-emotional responses.


Assuntos
Encéfalo/metabolismo , Potenciação de Longa Duração , Dor/fisiopatologia , Receptores Opioides/metabolismo , Nervo Isquiático/fisiopatologia , Transmissão Sináptica , Animais , Encéfalo/diagnóstico por imagem , Estimulação Elétrica , Potenciais Evocados , Feminino , Morfinanos/metabolismo , Fibras Nervosas Amielínicas , Vias Neurais/fisiopatologia , Dor/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
9.
Eur J Nucl Med Mol Imaging ; 37(6): 1174-80, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20157708

RESUMO

PURPOSE: The recent development in radiosynthesis of the (11)C-carbamate function increases the potential of [(11)C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor (kappa-OR) with PET. In the present study, [(11)C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. METHODS: Regional brain uptake kinetics of [(11)C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [(11)C]GR103545 was determined in cells transfected with cloned human opioid receptors. RESULTS: In vitro binding assays demonstrated a high affinity of GR103545 for kappa-OR (K(i) = 0.02 +/- 0.01 nM) with excellent selectivity over mu-OR (6 x 10(2)-fold) and) delta-OR (2 x 10(4)-fold). PET imaging revealed a volume of distribution (V(T)) pattern consistent with the known distribution of kappa-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. CONCLUSION: [(11)C]GR103545 is selective for kappa-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET.


Assuntos
Macaca mulatta , Piperazinas/metabolismo , Pirrolidinas/metabolismo , Receptores Opioides kappa/metabolismo , Vigília , Animais , Radioisótopos de Carbono , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Especificidade por Substrato
10.
J Med Chem ; 52(18): 5586-9, 2009 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-19694469

RESUMO

Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [(11)C]PEO binds with high affinity to mu and kappa-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the mu-OR after intravenous injection. Blocking studies with mu and kappa-OR selective compounds demonstrated that the binding of [(11)C]PEO is saturable and selective to the mu-OR in rat brain.


Assuntos
Morfinanos/síntese química , Morfinanos/farmacologia , Tomografia por Emissão de Pósitrons , Receptores Opioides/agonistas , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Células CHO , Radioisótopos de Carbono/química , Cricetinae , Cricetulus , Humanos , Cinética , Masculino , Morfinanos/metabolismo , Ratos , Ratos Wistar , Receptores Opioides/metabolismo , Especificidade por Substrato
11.
Pain ; 140(3): 456-64, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19004552

RESUMO

It has been suggested that spinal cord long-term potentiation (LTP) may contribute to hypersensitivity and hyperalgesia. We have investigated if noxious stimulus-induced spinal cord LTP might have a long lasting effect on supraspinal neuronal activity. First, we verified that spinal LTP was induced by electrical high frequency stimuli (HFS) conditioning applied to the sciatic nerve. The C-fibre response in the dorsal horn reached a twofold increase 150 min after HFS (t-test, p<0.01, n=6). Then, to study the metabolic supraspinal activity following the same stimulation protocol, we used small animal positron emission tomography (PET) and the glucose analog [(18)F]-fluorodeoxyglucose (FDG). With this combined approach we measured changes in regional supraspinal activity at two time points in HFS conditioned and in sham animals; acute (immediately after HFS/sham, n=4) and late phase (150 min after HFS/sham, n=10). Comparisons between HFS and sham groups revealed that induction of spinal LTP was followed by an acute metabolic response in the primary somatosensory cortex (S1), but also various slower metabolic adaptations in brain regions involved in modulation of nociceptive signaling and descending inhibition, i.e., amygdala, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT) (t-test, p<0.05). The study demonstrates that PET may be used as an in vivo method to study regional brain metabolic activity between different conditions. It is concluded that noxious sciatic stimuli which induce spinal cord LTP also affect supraspinal metabolic activity. We suggest that these changes might illustrate a supraspinal maladaptive dysfunction involved in pain hypersensitivity and hyperalgesia.


Assuntos
Encéfalo/fisiopatologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Dor/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Estimulação Elétrica , Metabolismo Energético/fisiologia , Feminino , Fluordesoxiglucose F18 , Hiperalgesia/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Dor/diagnóstico por imagem , Dor/metabolismo , Medição da Dor/métodos , Limiar da Dor/fisiologia , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiopatologia , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/fisiopatologia , Tempo
12.
Front Neuroinform ; 1: 4, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18974799

RESUMO

Tomographic neuroimaging techniques allow visualization of functionally and structurally specific signals in the mouse and rat brain. The interpretation of the image data relies on accurate determination of anatomical location, which is frequently obstructed by the lack of structural information in the data sets. Positron emission tomography (PET) generally yields images with low spatial resolution and little structural contrast, and many experimental magnetic resonance imaging (MRI) paradigms give specific signal enhancements but often limited anatomical information. Side-by-side comparison of image data with conventional atlas diagram is hampered by the 2-D format of the atlases, and by the lack of an analytical environment for accumulation of data and integrative analyses. We here present a method for reconstructing 3-D atlases from digital 2-D atlas diagrams, and exemplify 3-D atlas-based analysis of PET and MRI data. The reconstruction procedure is based on two seminal mouse and brain atlases, but is applicable to any stereotaxic atlas. Currently, 30 mouse brain structures and 60 rat brain structures have been reconstructed. To exploit the 3-D atlas models, we have developed a multi-platform atlas tool (available via The Rodent Workbench, http://rbwb.org) which allows combined visualization of experimental image data within the 3-D atlas space together with 3-D viewing and user-defined slicing of selected atlas structures. The tool presented facilitates assignment of location and comparative analysis of signal location in tomographic images with low structural contrast.

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