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1.
Nat Protoc ; 15(4): 1525-1541, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111986

RESUMO

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.


Assuntos
Técnicas de Química Sintética/métodos , Cobre/química , Radioisótopos de Flúor/química , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Automação , Ftalazinas/síntese química , Ftalazinas/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
2.
Chem Commun (Camb) ; 56(5): 723-726, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31840690

RESUMO

A new prosthetic group is reported for 18F-labelling of peptides and proteins based on the chemoselective ligation of potassium acyltrifluoroborates (KATs) and hydroxylamines without any detectable 18F/19F isotope exchange at the acyltrifluoroborate moiety. The new building block is appended via a common amide bond at room temperature with no need for protecting groups which enables an effective orthogonal 18F-radiolabelling.


Assuntos
Boratos/química , Radioisótopos de Flúor/química , Marcação por Isótopo/métodos , Peptídeos/química , Proteínas/química , Piridinas/química , Animais , Indicadores e Reagentes/química , Masculino , Camundongos Endogâmicos C57BL , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Proteínas/metabolismo , Compostos Radiofarmacêuticos/química , Temperatura
3.
Eur J Med Chem ; 183: 111730, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563014

RESUMO

Designing novel 18F-labeled amino acid derivatives for targeted amino acid transporters is an attractive strategy for the development of therapeutic and diagnostic agents for cancer therapy. In this work, we have developed a novel 3-fluoropropyl analog of arginine, namely, (2S,4S)4-[18F]FPArg, [18F]1, to be used as a probe for studying arginine metabolism. Optically pure and labeled with 18F and 19F, (2S,4S)4-(3-fluoropropyl)arginine was synthesized and isolated in high radiochemical purity (>95%). In vitro uptake assays in human MCF-7 cells revealed that [18F]1 enters cells mainly via sodium-independent cationic amino acid transporters and was inhibited >62% by arginine. [18F]1 showed a high cellular uptake of 7.3 ±â€¯0.24% and 6.07 ±â€¯0.3% uptake/100 mg protein after incubation in MCF-7 and MDA-MB-231 cells for 120 min, respectively. In vivo biodistribution studies demonstrated that [18F]1 provided high tumor uptake and high tumor to muscle ratios (5:1 at the 30 and 60 min time points). In vivo PET imaging studies demonstrated tumor-specific uptake in nude mice bearing MCF-7 breast tumors with an excellent tumor-to-muscle ratio. These results suggest that [18F]1 is a promising tracer for clinical breast cancer imaging and may be used to diagnose and monitor diseases that are associated with arginine metabolism.


Assuntos
Arginina/análogos & derivados , Arginina/síntese química , Neoplasias da Mama/diagnóstico por imagem , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Animais , Arginina/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Estabilidade de Medicamentos , Feminino , Humanos , Camundongos Nus , Estrutura Molecular , Compostos Radiofarmacêuticos/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual
4.
Biomed Pharmacother ; 119: 109454, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31526971

RESUMO

OBJECTIVE: The aim of this study was to evaluate the application of 18F-flortanidazole (18F-HX4)/18F-fluoromisonidazole (18F-FMISO) - based micro positron emission tomography/computed tomography (PET/CT) for imaging of tumor hypoxia and radiotherapy-associated changes in mice. MATERIALS AND METHODS: Radiotracer-based cellular uptake was performed to explore the correlation between radiotracer uptake and hypoxia state in cells. Animal models were established using subcutaneous injection of the human breast cancer line (MDA-MB-231) in a nude mouse. The effect of radiotherapy on tumor xenograft was assessed by measuring the tumor volume and mouse survival time. Meanwhile, mice with xenograft were imaged with 18F-FMISO and18F-HX4 PET/CT before and after radiotherapy. Tumor-to-normal muscle ratio (T/N) of 18F-FMISO and18F-HX4 maximum uptake was calculated by selecting a region of interest. Changes in tumor biology were assessed with immunohistochemical staining; T/N (18F-FMISO) and T/N (18F-HX4) were analyzed in relation to tumor volume, survival time, and the expression of tumor biomarkers, including hypoxia-inducible factor (HIF)-1α, glucose transporter (Glut-1) and the proliferation antigen Ki67. RESULTS: Higher tracer uptake (both 18F-FMISO and 18F-HX4) was observed in hypoxic cells compared to oxygenated cell. The in vivo study suggested that both T/N (18F-FMISO) and T/N (18F-HX4) were positively correlated with tumor hypoxia volume (p = 0.014 and p = 0.009, respectively), but negatively associated with survival time (p = 0.012 and p = 0.007, respectively). HIF-1α, Glut-1 and Ki67 expression in tumors were downregulated after radiotherapy. T/N (18F-HX4) was correlated with the expression of hypoxia marker HIF-1α in xenografts (r = 0.768, p = 0.025); while T/N (18F-FMISO) was moderately correlated with the expressions of Ki67 (r = 0.412, p = 0.041). No significant correlation was detected between Glut-1 expression and T/N (18F-FMISO) or T/N (18F-HX4) (r = 0.511, p = 0.097 and r=0.562, p = 0.126, respectively). CONCLUSIONS: Both 18F-HX4 and 18F-FMISO PET/CT can be used as biomarkers for tumor hypoxia and radiotherapy-associated changes. The clinical utilization of these two PET tracers needs to be further validated.


Assuntos
Azóis/química , Radioisótopos de Flúor/química , Misonidazol/análogos & derivados , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Hipóxia Tumoral , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Modelos Lineares , Camundongos Endogâmicos BALB C , Camundongos Nus , Misonidazol/química , Análise Multivariada , Tomografia Computadorizada por Raios X , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Molecules ; 24(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394799

RESUMO

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the 18F chemical toolbox gave aluminum [18F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [18F][AlF]2+ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [18F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [18F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [18F]AlF labeling applications through a description of the various [18F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.


Assuntos
Alumínio/química , Quelantes , Radioisótopos de Flúor/química , Radioisótopos de Gálio/química , Marcação por Isótopo , Animais , Biomarcadores , Quelantes/química , Compostos de Flúor/química , Humanos , Imagem Molecular/métodos , Estrutura Molecular , Peptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Conformação Proteica
6.
Chem Commun (Camb) ; 55(70): 10400-10403, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31402360

RESUMO

We report the first pretargeting in vivo study using the Strain-Promoted Sydnone-Alkyne Cycloaadition (SPSAC) reaction. The injection of a fluorine-18 labeled cyclooctyne three days after cetuximab bearing chlorosydnone moieties allowed a significant detection of the tumor by PET imaging suggesting an efficient click reaction inside the tumoral site. With a kinetic constant superior to 300 M-1 s-1, the SPSAC reaction might be an interesting tool, in addition to tetrazine-cyclooctene ligation, for in vivo chemistry.


Assuntos
Alquinos/química , Química Click/métodos , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Ciclização , Xenoenxertos , Humanos , Camundongos
7.
Neurochem Res ; 44(9): 2092-2102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377996

RESUMO

The aim of this study was to evaluate the diagnostic efficacy of 18F-FDG PET/MRI in two different peripheral neuropathic pain models using the injured rat sciatic nerves. Twelve rats, with operation on left sciatic nerves, were evenly divided into three groups: sham surgery (control group), crushing injury and chronic constriction injury (CCI) (experimental groups). The nerve damage was assessed at 3 weeks postoperatively using following methods: paw withdrawal threshold values (RevWT), maximum standardized uptake values on PET/MRI images (SUVR), and counting the number of myelinated axons in proximal and distal sites of nerve injury (MAxR). The results were quantified and statistically analyzed. Compared to the control group, the crushing injury demonstrated significant differences in RevWT (p < 0.0001) and SUVR (p = 0.027) and the CCI group demonstrated significant differences in RevWT (p < 0.0001), SUVR (p = 0.001) and MAxR (p = 0.048). There were no significant differences between the two experimental groups for all assessments. Correlation analysis demonstrated that RevWT and SUVR assessments were highly correlated (r = -- 0.710, p = 0.010), and SUVR and MAxR were highly correlated (r = 0.611, p = 0.035). However, there was no significant correlation between RevWT and MAxR. The PET scan may be a valuable imaging modality to enable noninvasive, objective diagnosis of neuropathic pain caused by peripheral nerve injury. Also, MRI fused with PET may help clarify the anatomic location of soft tissue structures, including the peripheral nerves.


Assuntos
Fluordesoxiglucose F18/química , Neuralgia/diagnóstico por imagem , Traumatismos dos Nervos Periféricos/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Neuropatia Ciática/diagnóstico por imagem , Animais , Radioisótopos de Flúor/química , Imagem por Ressonância Magnética , Masculino , Traumatismos dos Nervos Periféricos/patologia , Tomografia por Emissão de Pósitrons , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/patologia
8.
Chemistry ; 25(51): 11837-11841, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31310409

RESUMO

Bacterial production of ß-lactamases with carbapenemase activity is a global health threat. The active sites of class D carbapenemases such as OXA-48, which is of major clinical importance, uniquely contain a carbamylated lysine residue which is essential for catalysis. Although there is significant interest in characterizing this post-translational modification, and it is a promising inhibition target, protein carbamylation is challenging to monitor in solution. We report the use of 19 F NMR spectroscopy to monitor the carbamylation state of 19 F-labelled OXA-48. This method was used to investigate the interactions of OXA-48 with clinically used serine ß-lactamase inhibitors, including avibactam and vaborbactam. Crystallographic studies on 19 F-labelled OXA-48 provide a structural rationale for the sensitivity of the 19 F label to active site interactions. The overall results demonstrate the use of 19 F NMR to monitor reversible covalent post-translational modifications.


Assuntos
Compostos Azabicíclicos/química , Proteínas de Bactérias/química , Radioisótopos de Flúor/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/farmacologia , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Espectroscopia de Ressonância Magnética , Carbamilação de Proteínas , Processamento de Proteína Pós-Traducional , Inibidores de beta-Lactamases/química , beta-Lactamases/química , beta-Lactamases/metabolismo
9.
Mol Med Rep ; 20(3): 2276-2284, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257516

RESUMO

Glucagon­like peptide­1 (GLP­1) and its receptor (GLP­1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non­invasive method for monitoring GLP­1R expression. In the present study, a fluorine­18­labeled aluminum fluoride exendin­4 analog [18F­AlF conjugated with 1,4,7­triazacyclononanetriacetic acid (NOTA)­maleimide (MAL)­Cys40­exendin­4] was synthesized and evaluated in a rat MI/R model for GLP­1R imaging. NOTA­MAL­Cys40­exendin­4 was synthesized by coupling Cys40­exendin­4 with NOTA­MAL. NOTA­MAL­Cys40­exendin­4 was then conjugated with 18F­AlF to obtain 18F­AlF­NOTA­MAL­Cys40­exendin­4. The yield of 18F­AlF­NOTA­MAL­Cys40­exendin­4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP­1R and an appropriate signal­to­noise ratio. At 8 h post­MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post­MI/R compared with 8 h post­MI/R, but still remained higher compared with sham­operated groups (0.06±0.012 %ID/g; n=6). Pre­injected unlabeled exendin­4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18F­AlF­NOTA­MAL­Cys40­exendin­4 demonstrated favorable characteristics for GLP­1R imaging following MI/R. PET imaging using 18F­AlF­NOTA­MAL­Cys40­exendin­4 in rodent hearts after MI/R revealed a dynamic pattern of GLP­1R upregulation.


Assuntos
Exenatida/química , Radioisótopos de Flúor/química , Receptor do Peptídeo Semelhante ao Glucagon 1/análise , Coração/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Animais , Exenatida/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Masculino , Maleimidas/síntese química , Maleimidas/química , Tomografia por Emissão de Pósitrons/métodos , Ratos Sprague-Dawley
10.
Molecules ; 24(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261651

RESUMO

To further explore the scope of our recently developed "fluorination on Sep-Pak" method, we prepared two well-known positron emission tomography (PET) tracers 21-[18F]fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione furanyl norprogesterone ([18F]FFNP) and 16ß-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT). Following the "fluorination on Sep-Pak" method, over 70% elution efficiency was observed with 3 mg of triflate precursor of [18F]FFNP. The overall yield of [18F]FFNP was 64-72% (decay corrected) in 40 min synthesis time with a molar activity of 37-81 GBq/µmol (1000-2200 Ci/mmol). Slightly lower elution efficiency (~55%) was observed with the triflate precursor of [18F]FDHT. Fluorine-18 labeling, reduction, and deprotection to prepare [18F]FDHT were performed on Sep-Pak cartridges (PS-HCO3 and Sep-Pak plus C-18). The overall yield of [18F]FDHT was 25-32% (decay corrected) in 70 min. The molar activity determined by using mass spectrometry was 63-148 GBq/µmol (1700-4000 Ci/mmol). Applying this quantitative measure of molar activity to in vitro assays [18F]FDHT exhibited high-affinity binding to androgen receptors (Kd~2.5 nM) providing biological validation of this method.


Assuntos
Di-Hidrotestosterona/química , Radioisótopos de Flúor/química , Norpregnenos/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Halogenação , Humanos , Masculino , Espectrometria de Massas , Estrutura Molecular
11.
Eur J Med Chem ; 179: 449-469, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271958

RESUMO

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4ß2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/tratamento farmacológico , Radioisótopos de Flúor/química , Marcação por Isótopo , Agonistas Nicotínicos/farmacologia , Tomografia por Emissão de Pósitrons , Quinuclidinas/farmacologia , Triazóis/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
12.
Chem Commun (Camb) ; 55(50): 7259-7262, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31168526

RESUMO

A fluorine-18 doped bismuth upconversion luminescence (UCL) nanoprobe (18F-UNBOF) was quickly synthesized within 1 min at room temperature. 18F-UNBOF showed strong X-ray attenuation characteristics, stable radioactive 18F-labeling abilities and UCL properties. 18F-UNBOF nanoparticles could be utilized for tri-modal CT/PET/UCL imaging in vivo.


Assuntos
Bismuto/química , Radioisótopos de Flúor/química , Nanoestruturas/química , Meios de Contraste , Luminescência , Microscopia Eletrônica de Transmissão , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
13.
Eur J Med Chem ; 176: 410-418, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125895

RESUMO

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[11C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.


Assuntos
Isoquinolinas/metabolismo , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de GABA/metabolismo , Animais , Feminino , Radioisótopos de Flúor/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Marcação por Isótopo , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
14.
Molecules ; 24(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959762

RESUMO

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.


Assuntos
Resveratrol/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/administração & dosagem , Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/química , Humanos , Imuno-Histoquímica , Tomografia por Emissão de Pósitrons , Ratos , Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
15.
Nat Protoc ; 14(5): 1530-1545, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30980032

RESUMO

Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce 18F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [18F]FPEB, by either manual operation or an automated synthesis module. [18F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non-decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 ± 51.8 GBq/µmol; 18 ± 1.4 Ci/µmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, 18F labeling, and formulation of a product that is ready for injection require 2 h.


Assuntos
Técnicas de Química Sintética/métodos , Radioisótopos de Flúor/química , Hidrocarbonetos Aromáticos/química , Compostos Radiofarmacêuticos , Receptor de Glutamato Metabotrópico 5/metabolismo , Técnicas de Química Sintética/instrumentação , Desenho de Equipamento , Iodo/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
16.
Molecules ; 24(7)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987302

RESUMO

Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, ß-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.


Assuntos
Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons , Coloração e Rotulagem , Cromatografia em Camada Delgada , Radioquímica , Tetrazóis/química
17.
Chem Commun (Camb) ; 55(37): 5371-5374, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994648

RESUMO

A new radiotracer, [18F]NA3BF3, capable of rapid, stable, and catalyst-free complexation of aldehydes in vivo is reported. [18F]NA3BF3 was shown to bind aldehydes in live subjects using locally administered aldehyde-presenting microparticles, and was then applied to mapping aldehydic load in a mouse model of sepsis. [18F]NA3BF3 may enable the direct investigation of the chemical biology of aldehydes in living subjects, and may open avenues for the adoption of endogenous aldehydic load as an imaging biomarker of inflammatory pathology.


Assuntos
Aldeídos/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Animais , Boranos/química , Radioisótopos de Flúor/química , Rim/diagnóstico por imagem , Lipopolissacarídeos/toxicidade , Fígado/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos BALB C , Compostos Radiofarmacêuticos/síntese química , Sepse/diagnóstico , Sepse/diagnóstico por imagem , ortoaminobenzoatos/química
18.
Contrast Media Mol Imaging ; 2019: 5635269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30983920

RESUMO

The gonadotropin-releasing hormone (GnRH) receptor is overexpressed in the majority of tumors of the human reproductive system. The purpose of this study was to develop an 18F-labeled peptide for tumor GnRH receptor imaging. In this study, the GnRH (pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2) peptide analogues FP-d-Lys6-GnRH (FP = 2-fluoropropanoyl) and NOTA-P-d-Lys6-GnRH (P = ethylene glycol) were designed and synthesized. The IC50 values of FP-d-Lys6-GnRH and NOTA-P-d-Lys6-GnRH were 2.0 nM and 56.2 nM, respectively. 4-Nitrophenyl-2-[18F]fluoropropionate was conjugated to the ε-amino group of the d-lysine side chain of d-Lys6-GnRH to yield the new tracer [18F]FP-d-Lys6-GnRH with a decay-corrected yield of 8 ± 3% and a specific activity of 20-100 GBq/µmol (n=6). Cell uptake studies of [18F]FP-d-Lys6-GnRH in GnRH receptor-positive PC-3 cells and GnRH receptor-negative CHO-K1 cells indicated receptor-specific accumulation. Biodistribution and PET studies in nude mice bearing PC-3 xenografted tumors showed that [18F]FP-d-Lys6-GnRH was localized in tumors with a higher uptake than in surrounding muscle and heart tissues. Furthermore, the metabolic stability of [18F]FP-d-Lys6-GnRH was determined in mouse blood and PC-3 tumor homogenates at 1 h after tracer injection. The presented results indicated a potential of the novel tracer [18F]FP-d-Lys6-GnRH for tumor GnRH receptor imaging.


Assuntos
Radioisótopos de Flúor/química , Peptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Receptores LHRH/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo
19.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022852

RESUMO

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.


Assuntos
Complexos de Coordenação/administração & dosagem , Imagem Molecular , Peptídeos Cíclicos/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptores CXCR4/genética , Animais , Linhagem Celular Tumoral , Complexos de Coordenação/química , Radioisótopos de Flúor/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Camundongos , Peptídeos Cíclicos/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores CXCR4/química , Ensaios Antitumorais Modelo de Xenoenxerto
20.
ChemMedChem ; 14(9): 982-993, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900397

RESUMO

Translocator protein (TSPO) is a biomarker of neuroinflammation, which is a hallmark of many neurodegenerative diseases and has been exploited as a positron emission tomography (PET) target. Carbon-11-labelled PK11195 remains the most applied agent for imaging TSPO, despite its short-lived isotope and low brain permeability. Second-generation radiotracers show variance in affinity amongst subjects (low-, mixed-, and high-affinity binders) caused by the genetic polymorphism (rs6971) of the TSPO gene. To overcome these limitations, a new structural scaffold was explored based on the TSPO pharmacophore, and the analogue with a low-affinity binder/high-affinity binder (LAB/HAB) ratio similar (1.2 vs. 1.3) to that of (R)-[11 C]PK11195 was investigated. The synthesis of the reference compound was accomplished in six steps and 9 % overall yield, and the precursor was prepared in eight steps and 8 % overall yield. The chiral separation of the reference and precursor compounds was performed using supercritical fluid chromatography with >95 % ee. The absolute configuration was determined by circular dichroism. Optimisation of reaction conditions for manual radiolabelling revealed acetonitrile as a preferred solvent at 100 °C. Automation of this radiolabelling method provided R and S enantiomers in respective 21.3±16.7 and 25.6±7.1 % decay-corrected yields and molar activities of 55.8±35.6 and 63.5±39.5 GBq µmol-1 (n=3). Injection of the racemic analogue into a healthy rat confirmed passage through the blood-brain barrier.


Assuntos
Radioisótopos de Flúor/química , Polimorfismo Genético , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Receptores de GABA/química , Animais , Humanos , Estudo de Prova de Conceito , Ligação Proteica , Ratos , Receptores de GABA/metabolismo , Estereoisomerismo
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