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INTRODUCTION: The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with [18F]FNM using PET/CT images. This novel radiotracer targeting NMDA receptor has potential for investigation for neurological and psychiatric diseases. METHODS: Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations). RESULTS: The [18F]FNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11⯵Sv/MBq and 4.65⯵Sv/MBq for female and male human dosimetric models, respectively. CONCLUSIONS: This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers.
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Memantina/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Imagem Corporal Total , Animais , Proteínas Sanguíneas/metabolismo , Estabilidade de Medicamentos , Feminino , Humanos , Memantina/síntese química , Memantina/metabolismo , Memantina/farmacocinética , Radiometria , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
INTRODUCTION: Cell transplantation is an innovative therapeutic approach after brain injury to compensate for tissue damage. To have real-time longitudinal monitoring of intracerebrally grafted cells, we explored the feasibility of a molecular imaging approach using thymidine kinase HSV1-TK gene encoding and [18F]FHBG as a reporter probe to image enzyme expression. METHODS: A stable neuronal cell line expressing HSV1-TK was developed with an optimised mammalian expression vector to ensure long-term transgene expression. After [18F]FHBG incubation under defined parameters, calibration ranges from 1 X 104 to 3 X 106 Neuro2A-TK cells were analysed by gamma counter or by PET-camera. In parallel, grafting with different quantities of [18F]FHBG prelabelled Neuro2A-TK cells was carried out in a rat brain injury model induced by stereotaxic injection of malonate toxin. Image acquisition of the rats was then performed with PET/CT camera to study the [18F]FHBG signal of transplanted cells in vivo. RESULTS: Under the optimised incubation conditions, [18F]FHBG cell uptake rate was around 2.52%. In-vitro calibration range analysis shows a clear linear correlation between the number of cells and the signal intensity. The PET signal emitted into rat brain correlated well with the number of cells injected and the number of surviving grafted cells was recorded via the in-vitro calibration range. PET/CT acquisitions also allowed validation of the stereotaxic injection procedure. Technique sensitivity was evaluated under 5 X 104 grafted cells in vivo. No [18F]FHBG or [18F]metabolite release was observed showing a stable cell uptake even 2 h post-graft. CONCLUSION: The development of this kind of approach will allow grafting to be controlled and ensure longitudinal follow-up of cell viability and biodistribution after intracerebral injection.
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Lesões Encefálicas/diagnóstico por imagem , Vetores Genéticos/metabolismo , Herpesvirus Humano 1/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/metabolismo , Timidina Quinase/genética , Animais , Encéfalo/diagnóstico por imagem , Lesões Encefálicas/patologia , Linhagem Celular , Transplante de Células , Modelos Animais de Doenças , Radioisótopos de Flúor/química , Vetores Genéticos/genética , Guanina/análogos & derivados , Guanina/síntese química , Guanina/metabolismo , Humanos , Camundongos , Compostos Radiofarmacêuticos/síntese química , Ratos , Ratos Sprague-Dawley , Timidina Quinase/metabolismoRESUMO
In this study, we describe the radiosynthesis of [18F]AV1451 in terms of its pharmaceutical quality and characterise its physical and biological properties. We performed an in vitro serum stability study in fresh human plasma and a plasma protein binding study. The radiochemical yield was 24% (decay corrected), and the product met all regulatory quality requirements. We found that this compound is stable in fresh human plasma and binds tightly to plasma proteins, especially lipoproteins.
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Carbolinas/síntese química , Radioisótopos de Flúor/química , Compostos Radiofarmacêuticos/síntese química , Proteínas Sanguíneas/metabolismo , Carbolinas/sangue , Carbolinas/química , Cromatografia Líquida de Alta Pressão , Humanos , Lipoproteínas/metabolismo , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico por imagem , Ligação Proteica , Ensaio Radioligante , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Reprodutibilidade dos Testes , Espectrofotometria UltravioletaRESUMO
INTRODUCTION: The N-methyl-D-aspartate receptor (NMDAr) is an ionotropic receptor that mediates excitatory transmission. NMDAr overexcitation is thought to be involved in neurological and neuropsychiatric disorders such as Alzheimer disease and schizophrenia. We synthesized [(18)F]-fluoroethylnormemantine ([(18)F]-FNM), a memantine derivative that binds to phencyclidine (PCP) sites within the NMDA channel pore. These sites are primarily accessible when the channel is in the active and open state. METHODS: Radiosynthesis was carried out using the Raytest® SynChrom R&D fluorination module. Affinity of this new compound was determined by competition assay. We ran a kinetic study in rats and computed a time-activity curve based on a volume-of-interest analysis, using CARIMAS® software. We performed an ex vivo autoradiography, exposing frozen rat brain sections to a phosphorscreen. Adjacent sections were used to detect NMDAr by immunohistochemistry with an anti-NR1 antibody. As a control of the specificity of our compound for NMDAr, we used a rat anesthetized with ketamine. Correlation analysis was performed with ImageJ software between signal of autoradiography and immunostaining. RESULTS: Fluorination yield was 10.5% (end of synthesis), with a mean activity of 3145 MBq and a specific activity above 355 GBq/µmol. Affinity assessment allowed us to determine [(19)F]-FNM IC50 at 6.1 10(-6)M. [(18)F]-FMN concentration gradually increased in the brain, stabilizing at 40 minutes post injection. The brain-to-blood ratio was 6, and 0.4% of the injected dose was found in the brain. Combined ex vivo autoradiography and immunohistochemical staining demonstrated colocalization of NMDAr and [(18)F]-FNM (r=0.622, p<0.0001). The highest intensity was found in the cortex and cerebellum, and the lowest in white matter. A low and homogeneous signal corresponding to unspecific binding was observed when PCP sites were blocked with ketamine. CONCLUSIONS: [(18)F]-FNM appears to be a promising tracer for imaging NMDAr activity for undertaking preclinical studies in perspective of clinical detection of neurological or neuropsychological disorders.
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Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Memantina/análogos & derivados , Memantina/farmacocinética , Fenciclidina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Autorradiografia , Radioisótopos de Flúor/farmacocinética , Marcação por Isótopo , Cinética , Masculino , Taxa de Depuração Metabólica , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F]-fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink® (99m)Tc-tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices.
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Compostos Radiofarmacêuticos/síntese química , Rituximab/química , Tecnécio/química , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
BACKGROUND: Florbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria. METHODS: We recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito-frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed. RESULTS: Twenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests. CONCLUSIONS: These findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical ß-amyloid load.
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We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease.
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Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Etilenoglicóis , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Adulto , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Fluordesoxiglucose F18 , Humanos , Masculino , Fenótipo , Presenilina-1/genéticaRESUMO
BACKGROUND: Bone infection is a common issue in infectiology. The gold standard for evaluating bone infection is the white blood cell (WBC) scan. In our practice the WBC scan is coupled with a bone scan. Discordances in the results of these two examinations are a common occurrence in daily practice. We decided to investigate the meaning of these discordances. MATERIALS AND METHODS: Two hundred and ninety-six 99mTc-HMPA labelled white blood cells (WBC) and 99mTc-HMDP bone scanning (BS) examinations were performed in our department between 1997 and 2003 for evaluation of bone infection. Out of these 296 examinations, a first rating extracted 54 scans that were considered discordant. These 54 scans were reviewed by three observers. Clinical and paraclinical data were obtained for all the cases definitely considered as discordant by all three observers. RESULTS: The observers finally retained 18 cases as discordant from the initial 296 (6.1%). Thirteen patients were not infected,and five patients were considered infected based on clinical follow-up or bacteriological and histological data. For the 17 patients with WBC-, BS+, 4 (23.5%) were infected. CONCLUSION: Our study shows that in the vast majority(17 out of 18), discordances consist of a negative WBC scan with a positive bone scan. In these cases the accuracy of the WBC scan is diminished as 23.5% of the patients with a negative WBC and a positive bone scan are infected.
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Doenças Ósseas Infecciosas/sangue , Doenças Ósseas Infecciosas/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Leucócitos/diagnóstico por imagem , Reações Falso-Negativas , Humanos , Cintilografia , Estudos Retrospectivos , Coloração e Rotulagem , Tecnécio Tc 99m Exametazima , Medronato de Tecnécio Tc 99m/análogos & derivadosRESUMO
Analysis often reveals variability in the composition of ecstasy pills from pure 3,4-methylenedioxymethamphetamine (MDMA) to mixtures of MDMA derivatives, amphetamine, and other unidentified substances. For a comprehensive toxicological analysis one needs to know all steps to MDMA synthesis which may originate impurities. The aim of this study was to synthesise and determine the chemical-physical and in vitro biological properties of a series of MDMA derivatives.3,4-methylendioxyphenyl-2-nitropropene (MDNP) was obtained by condensation of piperonal with an excess of nitroethane in the presence of ammonium acetate. MDNP was then reduced to methylenedioxyamphetamine (MDA) by LiAlH3. All compounds were analysed using HPLC and spectroscopic technique [Raman, nuclear magnetic resonance (NMR), or infrared (IR)] at all the steps of synthesis. In addition, we assessed the biological potentials of these compounds by measuring in vitro their (i) blood cell/whole blood partition coefficient, (ii) binding to plasmatic proteins (Fbp), and (iii) membrane adsorption. Chemical structure was determined with antibody fluorescence polarisation immunoassay (FPIA). This study showed the presence of solid impurities, particularly of a neurotoxic compound of Al3+ in the final products. FPIA identified the aminoethane group close to the substituted benzene ring, but did not detect the two major precursors of MDMA: MDNP and piperonal. Raman spectroscopy is an attractive alternative technique to characterise ecstasy pills and it can identify stereoisomeric forms such as cis-MDNP and trans-MDNP, which exhibit signals at 1650 cm-1 and 1300 cm-1, respectively.
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N-Metil-3,4-Metilenodioxianfetamina/análise , Detecção do Abuso de Substâncias/métodos , Cromatografia Líquida de Alta Pressão , Humanos , Espectroscopia de Ressonância Magnética , N-Metil-3,4-Metilenodioxianfetamina/análogos & derivados , N-Metil-3,4-Metilenodioxianfetamina/síntese química , Espectrofotometria Infravermelho , Análise Espectral RamanRESUMO
OBJECTIVE: To assess the feasibility of synthesis of O-(2-[(18)F]-fluoroethyl)-l-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma. DESIGN: Prospective nonrandomized trial. PATIENTS: Twelve patients with suspicion of high-grade glioma. RESULTS: The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16 (0.75) for the 11 patients with glioblastoma. CONCLUSION: The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.
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Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tirosina/análogos & derivados , Humanos , Interpretação de Imagem Assistida por Computador , Processamento de Imagem Assistida por Computador , Estudos ProspectivosRESUMO
The aim of this biomedical trial was to clarify the physiological role of procalcitonin (PCT) in renal parenchyma apoptosis and fibrosis caused by acute childhood pyelonephritis. This prospective study enrolled 183 children. All children were treated with bi-therapy according to the French consensus on acute pyelonephritis treatment dated November 16, 1990: intra-vascular administration of ceftriaxone 50 mg/kg/day and netromicine 7 mg/kg/day during the first 48 hours, followed by specific antibiotherapy suited to antibiogram. On admission, PCT, C-reactive protein, and phospholipase A2 were quantified in serum. Scintigraphy monitoring with (99m)Tc-DMSA was performed on day 4 and 9 months later, in the presence of persistent abnormalities. On day 4, 78% presented renal parenchyma alterations and 30% renal fibrosis 9 months after admission. Paradoxically, PCT level was significantly lower in the presence of renal fibrosis due to cell apoptosis (4.19 vs 7.59 µgL(-1)). A significant increase in PCT indicated favorable progress (recovery 7.55 vs aggravation 3.34) and no difference between recovery and improvement. This result suggests the protective effect of PCT against apoptosis by nitric oxide down-regulation.
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Serum cystatin C (cysC) is a potential marker of the glomerular filtration rate (GFR) that has generated conflicting reports in children. A prospective study was conducted to assess the benefit of considering cysC together with serum creatinine (SCr) and demographic and morphologic characteristics to better estimate the 51Cr-ethylenediaminetetraacetate (EDTA) clearance (CL), i.e., the GFR. Plasma 51Cr-EDTA data from 100 children or young adults (range: 1.4-22.8 years old) were analyzed according to the population pharmacokinetic approach by using the nonlinear mixed effects model (NONMEM) program. The actual CL was compared to the CL predicted according to different covariate equations. The best covariate equation (+/-95% confidence interval) was: GFR (ml/min)=63.2(+/-3.4) . [(SCr (microM)/96)(-0.35 (+/-0.20))] . [(cysC (mg/l)/1.2)(-0.56 (+/-0.19))] . [(body weight (kg)/45)(0.30 (+/-0.17))] . [age (years)/14)(0.40 (+/-0.16))]. This equation was associated with a less biased and more precise estimation than the Schwartz equation. CysC improves the estimation of the GFR in children if considered with other covariates within the mathematical formula.
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Creatinina/sangue , Cistatinas/sangue , Taxa de Filtração Glomerular , Adolescente , Adulto , Criança , Pré-Escolar , Radioisótopos de Cromo , Cistatina C , Ácido Edético/metabolismo , Feminino , Humanos , Lactente , MasculinoRESUMO
UNLABELLED: (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methyl-phenyl) nortropane (PE2I), a cocaine analog, is a new, highly specific tracer for imaging dopamine transporter labeled with (123)I for in vivo SPECT. Its reversible binding on dopamine transporter and its rapid kinetics allow quantification of its binding potential according to a 3-compartment model. For quantification of distribution volume of reversible tracer, Logan developed a noninvasive and graphical method that allows accurate estimation of binding potential. In this study, we performed (123)I-PE2I SPECT on healthy volunteers and patients with Parkinson's disease (PD) to validate the Logan graphical method for quantification of (123)I-PE2I binding and to analyze the relationship between (123)I-PE2I SPECT and clinical features of this frequent degenerative disease. METHODS: Eight PD patients (3 women, 5 men; mean age, 64 +/- 7.9 y; disease duration range, 1-8 y, Hoehn and Yahr stage range, 1-2.5) and 8 age-matched healthy volunteers (4 women, 4 men; mean age, 61.5 +/- 9.5 y) were included in 2 centers and studied with SPECT. Four sequential SPECT imaging sessions of 15-min duration were performed from 5 to 65 min after bolus injection of 140 +/- 30 MBq of (123)I-PE2I. RESULTS: The kinetics of PE2I in healthy volunteers and PD patients were rapid, and the Logan graphical method allowed quantification of distribution volume ratio (DVR) in the caudate nucleus and putamen. (123)I-PE2I striatal specific binding was significantly reduced in PD patients, compared with healthy volunteers, in the caudate and putamen. The decrease of DVR in the putamen was significantly and inversely correlated to disease duration and Hoehn and Yahr stage. In asymmetric PD patients, (123)I-PE2I uptake was significantly more reduced in the putamen contralateral to the side with predominant clinical symptoms. However, (123)I-PE2I uptake was also significantly reduced in the ipsilateral putamen, compared with that in healthy volunteers, suggesting that (123)I-PE2I SPECT can detect nigrostriatal degeneration before the appearance of clinical symptoms. CONCLUSION: Our data indicate that the Logan graphical method is accurate for noninvasive quantification of PE2I and that (123)I-PE2I SPECT is a useful quantitative method for accurate estimation of nigrostriatal dopaminergic nerve terminal degeneration. The close relationships between SPECT findings and clinical data suggest that this method is useful for objectively following the progression of PD and for assessing the effect of potential neuroprotective treatments. Finally, our findings suggest that (123)I-PE2I SPECT can be used for preclinical and early diagnosis of PD.
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Radioisótopos do Iodo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/análise , Proteínas do Tecido Nervoso , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismoRESUMO
The aim of this study was to develop a method to predict the glomerular filtration rate (GFR) in children by using the population pharmacokinetic approach. This powerful approach is widely used for drug development in order to study relationships between patients' characteristics (demographic, morphological, biological covariates) and pharmacokinetic parameters. For the first time, (51)Cr-EDTA plasma concentrations from 64 children (development data set) were analyzed using the Non-linear Mixed Effects Model (NONMEM) program to determine the most appropriate equation to relate (51)Cr-EDTA clearance (as a measurement of GFR) and patient characteristics. The most predictive equation was based on body weight, square height, and plasma creatinine (PCr, determined by the Jaffé method). This equation was then validated using the data from a further 33 patients. This equation produced estimates of GFR that were less biased and more precise than those obtained using the widely used Schwartz formula. The coefficient of correlation between estimated and actual GFR was 0.83, and the 10th to 90th percentiles for percentage errors were -20% to +30%. Finally, analysis of the whole data set (97 patients) led to an equation (i.e., GFR (ml/min)=[56.7 x Body weight (kg)+0.142 x Length(2)(cm)]/PCr ( microM)) very similar to that obtained from the development data set. This equation would be useful for estimating GFR in children when isotopic determination of the (51)Cr-EDTA clearance cannot be performed.
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Taxa de Filtração Glomerular/fisiologia , Adolescente , Adulto , Algoritmos , Quelantes , Criança , Pré-Escolar , Radioisótopos de Cromo , Ácido Edético , Feminino , Humanos , Lactente , Masculino , Dinâmica não Linear , Farmacocinética , Estudos Prospectivos , Valores de ReferênciaRESUMO
A number of pre-clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side-effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I-Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I-Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long-term follow-up (average 4.5 months), five no longer required the I-Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I-Th morphine intake and five were stabilized until the end of their follow-up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met-enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long-term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.