RESUMO
Alzheimer's disease (AD) is the most common type of human dementia and is responsible for over 60% of diagnosed dementia cases worldwide. Abnormal deposition of ß-amyloid and the accumulation of neurofibrillary tangles have been recognised as the two pathological hallmarks targeted by AD diagnostic imaging as well as therapeutics. With the progression of pathological studies, the two hallmarks and their related pathways have remained the focus of researchers who seek for AD diagnostic and therapeutic strategies in the past decades. In this work, we reviewed the development of the AD biomarkers and their corresponding target-specific small molecule drugs for both diagnostic and therapeutic applications, underlining their success, failure, and future possibilities.
Assuntos
Doença de Alzheimer , Amiloidose , Biomarcadores , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/diagnóstico , Amiloidose/metabolismo , Animais , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Peptídeos beta-Amiloides/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
PURPOSE: There is no guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using pharmacological agents (chemoprophylaxis) in patients undergoing skull base surgery. The aim of this study was to compare VTE and intracranial haematoma rates after skull base surgery in patients treated with/without chemoprophylaxis. METHODS: Review of prospective quaternary centre database including adults undergoing first-time skull base surgery (2009-2020). VTE was defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) within 6 months of surgery. Multivariate logistic regression was used to determine factors predictive of postoperative intracranial haematoma/VTE. Propensity score matching (PSM) was used in group comparisons. RESULTS: One thousand five hundred fifty-one patients were included with a median age of 52 years (range 16-89 years) and female predominance (62%). Postoperative chemoprophylaxis was used in 81% of patients at a median of 1 day postoperatively. There were 12 VTE events (1.2%), and the use of chemoprophylaxis did not negate the risk of VTE entirely (p > 0.99) and was highest on/after postoperative day 6 (9/12 VTE events). There were 18 intracranial haematomas (0.8%), and after PSM, chemoprophylaxis did not significantly increase the risk of an intracranial haematoma (p > 0.99). Patients administered chemoprophylaxis from postoperative days 1 and 2 had similar rates of intracranial haematomas (p = 0.60) and VTE (p = 0.60), affirmed in PSM. CONCLUSION: Postoperative chemoprophylaxis represents a relatively safe strategy in patients undergoing skull base surgery. We advocate a personalised approach to chemoprophylaxis and recommend it on postoperative days 1 or 2 when indicated.
Assuntos
Embolia Pulmonar , Tromboembolia Venosa , Adulto , Humanos , Feminino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/tratamento farmacológico , Estudos Prospectivos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológico , Fatores de Risco , Anticoagulantes/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Estudos Retrospectivos , Hematoma , Base do Crânio/cirurgiaRESUMO
PURPOSE: The aim of this national survey is to assess the current practice of functional septorhinoplasty (SRP) surgery in the UK and better inform future practice. METHODS: An ENT-UK approved questionnaire was sent out to all 135 consultant members of the British Society of Facial Plastic Surgery (BSFPS). Data was collected on numbers of functional SRPs performed on the NHS, use of outcome measures, psychology and photography support, antibiotic use, referral base and consenting practice. RESULTS: The response rate was 38.5%, with 52 out of 135 completed. The median number of annual SRP cases per surgeon was 40. Most surgeons (95%) used clinical photography as an outcome measure. However, 27% of the respondents use a subjective outcome measurement and 3% of them use an objective outcome measurement. Only 34% had access to psychology support and 60% receive their referrals from primary care. All surgeons counsel patients for aesthetic change, 15% mention CSF leak and 38% mention olfactory disturbance. The key comment from our respondents was to relabel the rhinoplasty procedure as a functional SRP procedure with the aim to remove it from the Procedures of Limited Clinical Value (PoLCV) list. CONCLUSION: The majority of our respondents perform a large proportion of the SRP surgeries in the UK with each of the respondents performing an average of 40 SRP surgeries per year. There is a need to recatergorise functional septorhinoplasty as a functional operation and recommend functional SRP surgery to be removed from the PoLCV list.
Assuntos
Otolaringologia/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Prática Profissional/estatística & dados numéricos , Rinoplastia/estatística & dados numéricos , Cirurgia Plástica/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Pesquisas sobre Atenção à Saúde/estatística & dados numéricos , Humanos , Masculino , Septo Nasal/cirurgia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Projetos Piloto , Rinoplastia/métodos , Reino Unido/epidemiologiaRESUMO
N-(2-chloro-5-(S-2-[18 F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([18 F]GE-179), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [18 F]GE-179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8. The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 µg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18 F]GE-179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.
Assuntos
Radioquímica/métodos , Receptores de N-Metil-D-Aspartato/metabolismo , Automação , HumanosRESUMO
OBJECTIVES: Conebeam computed tomography (CBCT) imaging is commonly requested by dental implant surgeons, preoperatively, for patients being considered for dental implants. Incidental maxillary sinus findings often result in otolaryngology (ENT) referral for further assessment. CBCT findings include transient and benign mucosal changes that may not require any intervention and therefore unnecessarily delay implant surgery. We aim to define appropriateness criteria for ESS in the management of adult dental implant patients with incidental maxillary sinus findings on CBCT and provide guidance to both dental implant and ENT surgeons. DESIGN: The RAND/UCLA appropriateness methodology was used to develop and define the appropriateness criteria. SETTING: A virtual panel of 13 international experts in ESS. PARTICIPANTS: The expert panel completed two rounds of a modified Delphi ranking process for nine clinical scenarios, considering various factors affecting decision-making processes. MAIN OUTCOME MEASURES: To define appropriateness criteria for ESS in adult dental implant patients who have incidental maxillary sinus findings on CBCT. RESULTS: Patients with clinical symptoms and endoscopic findings of chronic rhinosinusitis together with an obstructed ostiomeatal complex (OMC) and concentric mucosal thickening of the ipsilateral maxillary sinus or pansinusitis were deemed appropriate candidates for ESS prior to their dental implant. ESS was not appropriate in asymptomatic patients with a patent OMC and mucosal thickening isolated to floor of the ipsilateral maxillary sinus. For uncertain scenarios, further discussion between dental implant and ENT surgeon should be considered. CONCLUSIONS: This study has developed and reported a list of appropriateness criteria to offer ESS in adult dental implant patients with incidental maxillary sinus findings on CBCT.
Assuntos
Tomografia Computadorizada de Feixe Cônico , Implantes Dentários , Endoscopia , Rinite/diagnóstico por imagem , Rinite/cirurgia , Sinusite/diagnóstico por imagem , Sinusite/cirurgia , Adulto , Doença Crônica , Técnica Delphi , Feminino , Humanos , Achados Incidentais , Masculino , Seleção de PacientesRESUMO
Cannabinoid type 2 receptor (CB2) is up-regulated on activated microglial cells and can potentially be used as a biomarker for PET-imaging of neuroinflammation. In this study the synthesis and pharmacological evaluation of novel fluorinated pyridyl and ethyl sulfone analogues of 2-(tert-butyl)-5-((2-fluoropyridin-4-yl)sulfonyl)-1-(2-methylpentyl)-1H-benzo[d]imidazole (rac-1a) are described. In general, the ligands showed low nanomolar potency (CB2 EC50 < 10 nM) and excellent selectivity over the CB1 subtype (>10 000×). Selected ligands 1d, 1e, 1g and 3l showing high CB2 binding affinity (Ki < 10 nM) were radiolabelled with fluorine-18 from chloropyridyl and alkyl tosylate precursors with good to high isolated radioactive yields (25-44%, non-decay corrected, at the end of synthesis). CB2-specific binding of the radioligand candidates [18F]-1d and [18F]-3l was assessed on rat spleen cryosections using in vitro autoradiography. The results warrant further in vivo evaluation of the tracer candidates as prospective CB2 PET-imaging agents.
RESUMO
Our recent investigations for the radiosynthesis of [18 F]fluoromethyl tosylate have highlighted that choice of quaternary methyl ammonium (QMA) cartridge used during the radiosynthesis can significantly impact the radiochemical yields. Often the details of the QMA cartridge used in fluourine-18 syntheses are not fully described. However, our studies demonstrate that the type, the size, and nature (method by which it has been conditioned) of the QMA cartridge used during the radiosynthesis can make a significant impact in the labelling efficiency. This paper investigates the use of three QMA cartridges and demonstrates that radiochemical yield (decay corrected) of [18 F]fluoromethyl tosylate can increase from 46% to 60% by simply changing the QMA cartridge (and leaving all other reagents and labelling conditions exactly the same). These learnings may be applied to improve the radiochemical yields of a number of [18 F]-fluorinated tracers (and synthons), where the labelling step is base-sensitive to increase the radiochemical yield, thereby significantly benefiting the radiochemistry and nuclear medicine community. This paper also highlights the necessity of the radiochemistry community to ensure the details of QMA cartridges used in fluorine-18 chemistry are fully and accurately described, since this will improve the translation of radiochemical methods from one laboratory to another.
Assuntos
Compostos de Amônio/química , Benzenossulfonatos/química , Benzenossulfonatos/síntese química , Radioisótopos de Flúor/química , Radioquímica/instrumentação , Técnicas de Química SintéticaRESUMO
18 F-radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18 F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).
Assuntos
Radioisótopos de Flúor/química , Gálio/química , Halogênios/química , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacocinética , Animais , Técnicas de Química Sintética , Feminino , Marcação por Isótopo , Mesilatos/química , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/química , Tomografia por Emissão de Pósitrons , Tiossemicarbazonas/síntese química , Distribuição TecidualRESUMO
We present the case of a patient with Cushing's syndrome secondary to ectopic ACTH secretion. A MR of the head showed a left-sided nasal mass extending down from the cribriform plate. The patient underwent endoscopic resection with nearly complete removal of the mass. Histological examination showed an ACTH-secreting olfactory neuroblastoma (ONB). The patient's cortisol levels returned to normal range after surgery and have remained normal for over a year. ONB is a rare cause for ectopic ACTH secretion. This case highlights the diagnostic and management difficulties in patients with ectopic ACTH secretion, and provides a brief review of ONB.
Assuntos
Síndrome de Cushing/etiologia , Estesioneuroblastoma Olfatório/complicações , Neoplasias Nasais/complicações , Síndrome de Cushing/patologia , Estesioneuroblastoma Olfatório/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasais/patologiaRESUMO
As part of a study to investigate the factors influencing the development of new, more effective metal-complex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]â 2 H2O has been prepared by reaction of 1-benzyl-1,4,7-triazacyclononane-4,7-dicarboxylic acid hydrochloride (H2Lâ HCl) with Ga(NO3)3â 9 H2O, which is a convenient source of Ga(III) for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]â 2 H2O are described, together with the crystal structure of [GaCl(L)]â MeCN. Fluorination of this complex by Cl(-)/F(-) exchange was achieved in high yield by treatment with KF in water at room temperature over 90â minutes, although the reaction was complete in approximately 30â minutes if heated to 80 °C, giving [GaF(L)]â 2 H2O in good yield. The same complex was obtained by hydrothermal synthesis from GaF3â 3 H2O and Li2L, and has been characterised by single-crystal X-ray analysis, IR, (1)H and (19)F{(1)H}â NMR spectroscopy and ESI(+) MS. Radiofluorination of the pre-formed [GaCl(L)]â 2 H2O has been demonstrated on a 210â nanomolar scale in aqueous NaOAc at pHâ 4 by using carrier-free (18)F(-), leading to 60-70% (18)F-incorporation after heating to 80 °C for 30â minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98-99% radiochemical purity. The [Ga(18)F(L)] is stable for at least 90â minutes in 10% EtOH/NaOAc solution at pHâ 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Groupâ 13 metal ion and co-ligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET.
Assuntos
Meios de Contraste/química , Complexos de Coordenação/química , Gálio/química , Compostos Aza/química , Meios de Contraste/síntese química , Meios de Contraste/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Radioisótopos de Flúor/química , Halogenação , Humanos , Concentração de Íons de Hidrogênio , Conformação Molecular , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismoRESUMO
Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [(123)I]- and [(125)I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[(123)I]-A85380 (see scheme, Boc = tert-butyloxycarbonyl, cod = 1,5-cyclooctadiene, TFA = trifluoroacetic acid).
Assuntos
Brometos/química , Diagnóstico por Imagem , Compostos Heterocíclicos/química , Radioisótopos do Iodo , Neurônios/metabolismo , Níquel/química , Receptores Nicotínicos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Estrutura Molecular , Neurônios/citologiaRESUMO
Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation yet to take place. Here we describe the synthesis of fluorinated 5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM) and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorination with non-decay-corrected radiochemical yields of 15 ± 6% and 18 ± 2% over 85 and 80 min, respectively, with high radiochemical purities (>97%) and molar activities (140-416 GBq/µmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.
Assuntos
Doenças Neuroinflamatórias , Tomografia por Emissão de Pósitrons , Ratos , Camundongos , Animais , Tomografia por Emissão de Pósitrons/métodos , Indóis/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Compostos Radiofarmacêuticos , Radioisótopos de Flúor/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/ß-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.
Assuntos
Endocanabinoides , Hidrolases , Animais , Endocanabinoides/metabolismo , Hidrolases/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Monoacilglicerol Lipases , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de PósitronsRESUMO
While the dire cardiometabolic consequences of the hypercaloric modern 'Western' diet are well known, there is not much information on the health impact of a high sucrose diet not inducing weight gain. Here, we tested the hypothesis that rats reared with intermittent binge access to sucrose in addition to normal chow would develop an inflammatory response in brain. To test this hypothesis, we undertook serial PET/MRI scans with the TSPO ligand [18F]DPA714 in a group of (n=9) rats at baseline and again after voluntarily consuming 5% sucrose solution three days a week for three months. Compared to a control group fed with normal chow (n=9), the sucrose rats indeed showed widespread increases in the availability of cerebral binding sites for the microglial marker, despite normal weight gain compared to the control diet group. Subsequent immunofluorescence staining of the brains confirmed the PET findings, showing a widespread 20% increase in the abundance of IBA-1-positive microglia with characteristic 'semi-activated' morphology in the binge sucrose rats, which had 23% lower density of microglial endpoints and 25% lower mean process length compared to microglia in the control rats with ordinary feeding. GFAP immunofluorescence showed no difference in astroglial coverage in the sucrose rats, except for a slight reduction in hypothalamus. The binge sucrose diet-induced neuroinflammation was associated with a significant elevation of white blood cell counts. Taking these results together, we find that long-term intake of sucrose in a binge paradigm, similar in sucrose content to the contemporary Western diet, triggered a low-grade systemic and central inflammation in non-obese rats. The molecular mechanism of this phenomenon remains to be established.
Assuntos
Encéfalo/patologia , Dieta/efeitos adversos , Sacarose Alimentar/efeitos adversos , Inflamação/patologia , Obesidade/patologia , Animais , Astrócitos/patologia , Gliose/sangue , Gliose/complicações , Gliose/patologia , Inflamação/sangue , Inflamação/complicações , Fígado/patologia , Masculino , Microglia/patologia , Obesidade/sangue , Obesidade/complicações , Ratos , Ratos WistarRESUMO
INTRODUCTION: The increase in expression of tryptophan 2, 3-dioxygenases (TDO) and indoleamine 2,3-dioxygenase (IDO) have been reported as potential tumor biomarkers. TDO and IDO are enzymes that catalyze the first and rate-limiting step of the kynurenine pathway. Positron emitting tomography (PET) tracers investigating the kynurenine pathway may allow for the detection of different disease pathologies in vivo including cancer. However, current PET tracers being developed for TDO and IDO have suffered from either multi-step low yielding syntheses or de-fluorination of the tracer in vivo. RESULTS: TDO inhibitors based on 6-fluoroindole with C3 substituents are a class of small molecules that have been shown to bind to TDO effectively, restore tryptophan concentration and decrease the production of immunosuppressive metabolites. The compound 6-fluoro-3-(pyridine-3-yl)-1H-indole has been reported to have high in vitro affinity for TDO. Herein we report the fully automated radiosynthesis of 6-[18F]fluoro-3-(pyridine-3-yl)-1H-indole [18F]4 using a copper-mediated nucleophilic 18F-fluorination resulting in a non-corrected yield of 5 to 6% of the tracer with a radiochemical purity of >99% after 4 h. Small animal dynamic PET/CT imaging of [18F]4 intravenously injected into normal C57BL/6 mice revealed rapid accumulation in heart and brain, reaching maximum occupancy in heart (10.9% ID/g) and brain (8.1% ID/g) at 1.75 min and 2.25 min, respectively. Furthermore, these in vivo studies revealed no de-fluorination of the tracer, as evidence by the absence of [18F]fluoride accumulation in bone. CONCLUSION: In vitro studies demonstrate that 4 has good affinity for hTDO and the radiolabeled analogue [18F]4 can be synthesized with suitable radiochemical yields. [18F]4 demonstrates good uptake in the brain and the radiolabeled compound shows no de-fluorination in vivo in C57BL/6 mice.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Transporte Biológico , Encéfalo/metabolismo , Catálise , Técnicas de Química Sintética , Cobre/química , Halogenação , Camundongos , Traçadores Radioativos , Radioquímica , Distribuição TecidualRESUMO
INTRODUCTION: Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABAa receptors (GABAaR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAaR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAaR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABAaR levels in the adult offspring. METHODS: C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [18F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry. RESULTS: In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABAaR in the olfactory bulbs. Immunohistochemistry detected reduced GABAaR in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE. CONCLUSION: Early moderate PEE may induce long-term alterations in the GABAaR system that persisted into adulthood.
Assuntos
Benzodiazepinas/química , Encéfalo/metabolismo , Etanol/toxicidade , Flumazenil/metabolismo , Radioisótopos de Flúor/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de GABA-A/metabolismo , Animais , Depressores do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Feminino , Flumazenil/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons/métodos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Distribuição TecidualRESUMO
Objective: To investigate the imaging and biodistribution of a novel zirconium-89 (89Zr)-labeled mouse anti-cd20 monoclonal antibody (mAb) in control and experimental autoimmune encephalomyelitis (EAE) mice following subcutaneous (s. c.) and intravenous (i.v.) administration. Background: Anti-cd20-mediated B-cell depletion using mAbs is a promising therapy for multiple sclerosis. Recombinant human myelin oligodendrocyte glycoprotein (rhMOG)-induced EAE involves B-cell-mediated inflammation and demyelination in mice. Design/Methods: C57BL/6J mice (n = 39) were EAE-induced using rhMOG. On Day 14 post EAE induction, 89Zr-labeled-anti-cd20 mAb was injected in control and EAE mice in the right lower flank (s.c.) or tail vein (i.v.). Positron emission tomography/computed tomography (PET/CT) imaging and gamma counting (ex vivo) were performed on Days 1, 3, and 7 to quantify tracer accumulation in the major organs, lymphatics, and central nervous system (CNS). A preliminary study was conducted in healthy mice to elucidate full and early kinetics of the tracer that were subsequently applied in the EAE and control mice study. Results:89Zr-labeled anti-cd20 mAb was effectively absorbed from s.c. and i.v. injection sites and distributed to all major organs in the EAE and control mice. There was a good correlation between in vivo PET/CT data and ex vivo quantification of biodistribution of the tracer. From gamma counting studies, initial tracer uptake within the lymphatic system was found to be higher in the draining lymph nodes (inguinal or subiliac and sciatic) following s.c. vs. i.v. administration; within the CNS a significantly higher tracer uptake was observed at 24 h in the cerebellum, cerebrum, and thoracic spinal cord (p < 0.05 for all) following s.c. vs. i.v. administration. Conclusions: The preclinical data suggest that initial tracer uptake was significantly higher in the draining lymph nodes (subiliac and sciatic) and parts of CNS (the cerebellum and cerebrum) when administered s.c. compared with i.v in EAE mice.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antígenos CD20/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Radioisótopos/farmacocinética , Zircônio/farmacocinética , Administração Intravenosa , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Injeções Subcutâneas , Taxa de Depuração Metabólica , Camundongos Endogâmicos C57BL , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos/química , Medula Espinal/diagnóstico por imagem , Medula Espinal/imunologia , Medula Espinal/metabolismo , Distribuição Tecidual , Zircônio/químicaRESUMO
INTRODUCTION: Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[18F]fluorobenzyl)cholylglycine ([18F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [18F]FBCGly and a proof-of-concept study by PET/MR in rats. METHODS: A radiosynthesis of [18F]FBCGly was developed based on reductive alkylation of glycine with 4-[18F]fluorobenzaldehyde followed by coupling to cholic acid. [18F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [18F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [18F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro. RESULTS: [18F]FBCGly was produced with a radiochemical purity of 96%⯱â¯1% and a non-decay corrected radiochemical yield of 1.0%⯱â¯0.3% (mean⯱â¯SD; nâ¯=â¯12). PET/MR studies showed that i.v.-administrated [18F]FBCGly underwent EHC within 40-60â¯min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [18F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [18F]FBCGly. No fluorine-18 metabolites of [18F]FBCGly were observed. CONCLUSION: We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [18F]FBCGly, and shown by PET/MR that [18F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET studies on the effect of drugs or diseases on the EHC of conjugated bile acids.
Assuntos
Ácidos e Sais Biliares/metabolismo , Circulação Êntero-Hepática , Radioisótopos de Flúor/química , Ácido Glicocólico/síntese química , Tomografia por Emissão de Pósitrons/métodos , Amidoidrolases/metabolismo , Animais , Técnicas de Química Sintética , Feminino , Radioisótopos de Flúor/metabolismo , Ácido Glicocólico/química , Ácido Glicocólico/metabolismo , Meia-Vida , Traçadores Radioativos , Radioquímica , Ratos , Ratos Sprague-DawleyRESUMO
Inflammatory skull base masses are enigmatic and often behaviourally unpredictable. We present a case of idiopathic hypertrophic pachymeningitis (IHP) forming a central skull base mass to illustrate the process required when one investigates such skull base lesions. This is the first description of mass forming or tumefactive IHP extending into the nasopharynx. A 32-year old woman presented with frontal headaches and nasal discharge. She then deteriorated and was admitted with worsening headaches, serosanguinous nasal discharge and bilateral ophthalmoplegia. Multimodality imaging confirmed a destructive central skull base soft tissue mass involving the posterior clivus, floor of sphenoid sinus, nasopharynx and extending into both cavernous sinuses. Unfortunately, the patient continued to deteriorate despite treatment with broad-spectrum antibiotics. Cerebrospinal fluid, blood tests and transnasal biopsies for histology and microbiology did not reveal a diagnosis. Further neuroimaging revealed extension of the mass. Early corticosteroid treatment demonstrated radical improvement although an initial reducing regime resulted in significant rebound deterioration. She was stable on discharge with slowly reducing low dose oral prednisolone and azathioprine. We discuss the complexity of this case paying special attention to the process followed in order to arrive at a diagnosis of idiopathic hypertrophic pachymeningitis based on both the clinical progression and the detailed analysis of serial skull base imaging. Knowledge of the potential underlying aetiologies, characteristic radiological features, common pathogens and the impact on blood serology can narrow the potential differentials and may avoid the morbidity associated with extensive resective procedures.
RESUMO
The reactions of the hydrated Group 13 fluorides, MF3·3H2O (M = Al, Ga or In) with 2,2':6',2''-terpyridyl, 2,2'-bipyridyl or 1,10-phenanthroline under hydrothermal conditions (180 °C/15 h) produced high yields of the complexes [MF3(terpy)]·3H2O, [MF3(bipy)(OH2)]·2H2O and [MF3(phen)(OH2)]. X-Ray crystal structures of [M'F3(terpy)]·3H2O (M' = Al or Ga), [M'F3(bipy)(OH2)]·2H2O and [GaF3(phen)(OH2)] show that all of them contain distorted octahedral geometries at the metal with mer-trifluoride coordination. Extensive H-bonding (FH-OH) links the molecules. The complexes have been further characterised by microanalysis, IR, (1)H, (19)F{(1)H} and (27)Al NMR spectroscopy. In contrast, reactions of the trifluorides with the acyclic triamine, N,N,N',N',N''-pentamethyldiethylenetriamine, under similar hydrothermal conditions results in cleavage of the triamine and ring-closure to form the 1,1,4-trimethylpiperazinium cation, [âMe2N(CH2)2NMe(CH2)2](+), with fluorometallate anions, and confirmed by X-ray analysis of [âMe2N(CH2)2NMe(CH2)2]2[Al2F8(OH2)2]·2H2O. The strongly H-bonded [GaF3(terpy)]·3H2O was also obtained by Cl/F exchange from [GaCl3(terpy)] and [NBu4]F or [K(2,2,2-crypt)]F. Crystallisation of a mixture of [NH4][PF6] and [GaF3(terpy)]·3H2O from aqueous solution produced the edge-bridged cationic complex, [{Ga(terpy)F}2(µ-F)2][PF6]2. The synthesis of the more sterically bulky [GaCl3((t)Bu3-terpy)] ((t)Bu3-terpy = 4,4'4''-tris-(t)Bu-2,2':6',2''-terpyridyl) and the crystal structure of [GaCl2((t)Bu3-terpy)][GaCl4], which contains a trigonal bipyramidal cation, are also reported.