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1.
Brain ; 145(3): 1098-1110, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-34528069

RESUMO

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.


Assuntos
Dor Crônica , Dor Lombar , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Dor Crônica/diagnóstico por imagem , Humanos , Dor Lombar/diagnóstico por imagem , Dor Lombar/metabolismo , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/metabolismo
2.
Handb Exp Pharmacol ; 271: 547-577, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34363128

RESUMO

Kappa opioid receptor (KOR) neuroimaging using positron emission tomography (PET) has been immensely successful in all phases of discovery and validation in relation to radiotracer development from preclinical imaging to human imaging. There are now several KOR-specific PET radiotracers that can be utilized for neuroimaging, including agonist and antagonist ligands, as well as C-11 and F-18 variants. These technologies will increase KOR PET utilization by imaging centers around the world and have provided a foundation for future studies. In this chapter, I review the advances in KOR radiotracer discovery, focusing on ligands that have been translated into human imaging, and highlight key attributes unique to each KOR PET radiotracer. The utilization of these radiotracers in KOR PET neuroimaging can be subdivided into three major investigational classes: the first, measurement of KOR density; the second, measurement of KOR drug occupancy; the third, detecting changes in endogenous dynorphin following activation or deactivation. Given the involvement of the KOR/dynorphin system in a number of brain disorders including, but not limited to, pain, itch, mood disorders and addiction, measuring KOR density in the living brain will offer insight into the chronic effects of these disorders on KOR tone in humans. Notably, KOR PET has been successful at measuring drug occupancy in the human brain to guide dose selection for maximal therapeutic efficacy while avoiding harmful side effects. Lastly, we discuss the potential of KOR PET to detect changes in endogenous dynorphin in the human brain, to elucidate neural mechanisms and offer critical insight into disease-modifying therapeutics. We conclude with comments on other translational neuroimaging modalities such as MRI that could be used to study KOR-dynorphin tone in the living human brain.


Assuntos
Tomografia por Emissão de Pósitrons , Receptores Opioides kappa , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Dinorfinas , Humanos , Ligantes
3.
Molecules ; 25(5)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32106419

RESUMO

The orexin receptor (OX) is critically involved in motivation and sleep-wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([11C]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 µM and 1.406 µM for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [11C]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [11C]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.


Assuntos
Encéfalo/diagnóstico por imagem , Neuroimagem , Receptores de Orexina/isolamento & purificação , Tomografia por Emissão de Pósitrons , Encéfalo/fisiologia , Humanos , Receptores de Orexina/genética , Sono/genética , Sono/fisiologia
4.
Mol Pharm ; 15(2): 695-702, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29298483

RESUMO

Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/µmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex ≫ white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.


Assuntos
Radioisótopos de Carbono , Clioquinol/análogos & derivados , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Doença de Alzheimer/patologia , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Clioquinol/administração & dosagem , Clioquinol/síntese química , Clioquinol/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Papio anubis , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética
5.
Chem Soc Rev ; 45(17): 4708-26, 2016 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-27276357

RESUMO

The positron-emitting radionuclide carbon-11 ((11)C, t1/2 = 20.3 min) possesses the unique potential for radiolabeling of any biological, naturally occurring, or synthetic organic molecule for in vivo positron emission tomography (PET) imaging. Carbon-11 is most often incorporated into small molecules by methylation of alcohol, thiol, amine or carboxylic acid precursors using [(11)C]methyl iodide or [(11)C]methyl triflate (generated from [(11)C]carbon dioxide or [(11)C]methane). Consequently, small molecules that lack an easily substituted (11)C-methyl group are often considered to have non-obvious strategies for radiolabeling and require a more customized approach. [(11)C]Carbon dioxide itself, [(11)C]carbon monoxide, [(11)C]cyanide, and [(11)C]phosgene represent alternative reactants to enable (11)C-carbonylation. Methodologies developed for preparation of (11)C-carbonyl groups have had a tremendous impact on the development of novel PET tracers and provided key tools for clinical research. (11)C-Carbonyl radiopharmaceuticals based on labeled carboxylic acids, amides, carbamates and ureas now account for a substantial number of important imaging agents that have seen translation to higher species and clinical research of previously inaccessible targets, which is a testament to the creativity, utility and practicality of the underlying radiochemistry.


Assuntos
Radioisótopos de Carbono/química , Oxigênio/química , Tomografia por Emissão de Pósitrons/instrumentação , Compostos Radiofarmacêuticos/química , Dacarbazina/análogos & derivados , Dacarbazina/química , Humanos , Estrutura Molecular , Temozolomida
6.
Mol Imaging ; 152016.
Artigo em Inglês | MEDLINE | ID: mdl-27553293

RESUMO

Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [(11)C]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [(11)C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [(11)C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.


Assuntos
Encéfalo/diagnóstico por imagem , Neuroimagem/métodos , Tetra-Hidronaftalenos/farmacologia , Animais , Bexaroteno , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Masculino , Tomografia por Emissão de Pósitrons , Primatas , Compostos Radiofarmacêuticos/química , Ratos , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/química
7.
J Am Chem Soc ; 137(2): 648-51, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25565277

RESUMO

A new radiosynthetic protocol for the preparation of [(11)C]aryl nitriles has been developed. This process is based on the direct reaction of in situ prepared L·Pd(Ar)X complexes (L = biaryl phosphine) with [(11)C]HCN. The strategy is operationally simple, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of [(11)C]nitrile-containing pharmaceuticals were prepared with high radiochemical efficiency.


Assuntos
Nitrilas/química , Compostos Organometálicos/química , Paládio/química , Fosfinas/química , Temperatura , Radioisótopos de Carbono/química , Cinética
8.
ACS Chem Neurosci ; 15(14): 2654-2661, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38916752

RESUMO

The extent of changes in functional connectivity (FC) within functional networks as a common feature across hallucinogenic drug classes is under-explored. This work utilized fMRI to assess the dissociative hallucinogens Psilocybin, a classical serotonergic psychedelic, and Salvinorin-A, a kappa-opioid receptor (KOR) agonist, on resting-state FC in nonhuman primates. We highlight overlapping and differing influence of these substances on FC relative to the thalamus, claustrum, prefrontal cortex (PFC), default mode network (DMN), and DMN subcomponents. Analysis was conducted on a within-subject basis. Findings support the cortico-claustro-cortical network model for probing functional effects of hallucinogens regardless of serotonergic potential, with a potential key paradigm centered around the claustrum, PFC, anterior cingulate cortices (ACC), and angular gyrus relationship. Thalamo-cortical networks are implicated but appear dependent on 5-HT2AR activation. Acute desynchronization relative to the DMN for both drugs was also shown. Our findings provide a framework to understand broader mechanisms at which hallucinogens in differing classes may impact subjects regardless of the target receptor.


Assuntos
Diterpenos Clerodânicos , Alucinógenos , Imageamento por Ressonância Magnética , Psilocibina , Alucinógenos/farmacologia , Diterpenos Clerodânicos/farmacologia , Animais , Psilocibina/farmacologia , Masculino , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Macaca mulatta , Rede de Modo Padrão/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Vias Neurais/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/diagnóstico por imagem
9.
Sci Rep ; 14(1): 9064, 2024 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643236

RESUMO

Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.


Assuntos
Demência Frontotemporal , Humanos , Progranulinas/metabolismo , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Epigênese Genética , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular/metabolismo
10.
ACS Cent Sci ; 10(5): 1105-1114, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38799654

RESUMO

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

11.
Bioorg Med Chem ; 20(3): 1337-45, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22249122

RESUMO

SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azetidinas/síntese química , Azetidinas/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/química , Radioisótopos/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Arginina Vasopressina/metabolismo , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , Receptores de Vasopressinas/análise
12.
ACS Chem Neurosci ; 10(1): 384-395, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30212182

RESUMO

Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND, binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BPND maps for three common KOR PET radioligands, the antagonists [11C]LY2795050 and [11C]LY2459989, and the agonist [11C]GR103545. We then measured changes in BPND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BPND was affected similarly between [11C]GR103545 and [11C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined, and we observed a persistent decrease in [11C]GR103545 BPND up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [11C]GR103545 BPND but did not change [11C]LY2459989 binding. This discrepancy was further examined in dose-response studies with each radiotracer as well as in vitro binding experiments.


Assuntos
Analgésicos Opioides/metabolismo , Benzamidas/metabolismo , Radioisótopos de Carbono/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Pirrolidinas/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Animais , Benzamidas/farmacologia , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Radioisótopos de Carbono/farmacologia , Relação Dose-Resposta a Droga , Masculino , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley
13.
Acta Pharm Sin B ; 9(6): 1204-1215, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31867166

RESUMO

The sigma-1 receptor (σ 1R) is a unique intracellular protein. σ 1R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ 1R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ 1R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ 1R 11C-labeled radioligands based on 6-hydroxypyridazinone, [11C]HCC0923 and [11C]HCC0929. Two radioligands have high affinities to σ 1R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds 13 and 15 (self-blocking). Of the two, [11C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ 1R agonist SA 4503 and σ 1R antagonist PD 144418. Both σ 1R ligands could extensively decreased the uptake of [11C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined in vivo. These studies demonstrated that two radioligands, especially [11C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ 1R in brain.

14.
Chem Sci ; 9(5): 1168-1172, 2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29675161

RESUMO

The first direct C-H 18F fluorination reaction of unactivated aliphatic sites using no-carrier-added [18F]fluoride is reported. Under the influence of a manganese porphyrin/iodosylbenzene system, a variety of unactivated aliphatic C-H bonds can be selectively converted to C-18F bonds. The mild conditions, broad substrate scope and generally inaccessible regiochemistry make this radio-fluorination a powerful alternate to established nucleophilic substitution for the preparation of 18F labeled radio tracers.

15.
ACS Chem Neurosci ; 9(2): 298-305, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29050469

RESUMO

As one of the major excitatory ion channels in the brain, NMDA receptors have been a leading research target for neuroscientists, physicians, medicinal chemists, and pharmaceutical companies for decades. Molecular imaging of NMDA receptors by means of positron emission tomography (PET) with [18F]GE-179 quickly progressed to clinical PET studies, but a thorough understanding of its binding specificity has been missing and has thus limited signal interpretation. Here a preclinical study with [18F]GE-179 in rodents and nonhuman primates (NHPs) is presented in an attempt to characterize [18F]GE-179 signal specificity. Rodent PET/CT was used to study drug occupancy and functional manipulation in rats by pretreating animals with NMDA targeted blocking/modulating drug doses followed by a single bolus of [18F]GE-179. Binding competition with GE-179, MK801, PCP, and ketamine, allosteric inhibition by ifenprodil, and brain activation with methamphetamine did not alter the [18F]GE-179 brain signal in rats. In addition, multimodal imaging with PET/MRI in NHPs was used to evaluate changes in radiotracer binding as a function of pharmacological challenges. Drug-induced hemodynamic changes were monitored simultaneously using functional MRI (fMRI). Comparisons of baseline and signal after drug challenge in NHPs demonstrated that the [18F]GE-179 signal cannot be manipulated in a predictable fashion in vivo. fMRI data acquired simultaneously with PET data supported this finding and provided evidence that radiotracer delivery is not altered by blood flow changes. In conclusion, the [18F]GE-179 brain signal is not readily interpretable in the context of NMDA receptor binding on the basis of the results shown in this study.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Compostos Radiofarmacêuticos , Receptores de N-Metil-D-Aspartato/metabolismo , Compostos de Sulfidrila , Animais , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Radioisótopos de Flúor , Hemodinâmica/efeitos dos fármacos , Ketamina/farmacologia , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/farmacologia , Imagem Multimodal , Fenciclidina/farmacologia , Piperidinas/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/farmacologia , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Compostos de Sulfidrila/farmacologia
16.
J Nucl Med ; 59(10): 1538-1543, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29853654

RESUMO

Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to noninvasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical analysis of novel compounds that could not otherwise be accomplished ex vivo. Although PET imaging with 16ß-18F-fluoro-5α-dihydrotestosterone (18F-FDHT) has successfully quantified AR levels clinically, no rodent model of 18F-FDHT imaging has been reported so far. One difference between humans and rodents is the absence in the latter of the sex hormone-binding globulin (SHBG), a glycoprotein that binds to testosterone in the bloodstream, Here, we explore the role of SHBG in developing a working model of rodent AR imaging. Methods: Three human prostate cancer cell lines and xenografts (LNCaP, 22Rv1, and PC3) were used to examine the uptake of free 18F-FDHT and SHBG-bound 18F-FDHT. Both ligands were examined for stability and competitive binding to AR over time in vitro before in vivo studies. PET/CT imaging was used to dynamically measure the uptake of both tracers over 4 h, whereas specificity was determined by competitive binding with the AR antagonist enzalutamide. Results: AR levels correlated with the uptake of both 18F-FDHT and SHBG-18F-FDHT in prostate cancer cell lines. Interestingly, whereas both free and SHBG-bound 18F-FDHT had a similar cellular accumulation at 1 and 2.5 h, SHBG-18F-FDHT accumulated at significantly higher levels after 4 h-evidence that receptor-mediated uptake of SHBG accounted for later time-point differences. This observation was also seen in 22Rv1 tumor-bearing mice, in which SHBG-18F-FDHT exhibited a significantly increased uptake (average tumor-to-background ratio [TBR], 1.62 ± 0.62) in comparison to unbound 18F-FDHT (TBR, 0.81 ± 0.08) at 4 h. Furthermore, the specificity of the SHBG-18F-FDHT accumulation at 4 h was demonstrated by a reduced tumor uptake after AR blockade with enzalutamide (TBR, 1.07 ± 0.13). Conclusion: Prebinding of 18F-FDHT to SHBG allows accurate and quantitative PET imaging of AR levels in murine models of prostate cancer. This procedure may permit the use of PET imaging to study the longitudinal effects of AR-targeting therapies, accelerating novel-drug development.


Assuntos
Transformação Celular Neoplásica , Di-Hidrotestosterona/análogos & derivados , Radioisótopos de Flúor , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Animais , Transporte Biológico , Linhagem Celular Tumoral , Di-Hidrotestosterona/metabolismo , Humanos , Masculino , Camundongos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Ligação Proteica
17.
J Med Chem ; 50(9): 2040-8, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17402722

RESUMO

Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.


Assuntos
Antineoplásicos/síntese química , Indenos/síntese química , Isoquinolinas/síntese química , Lactamas/síntese química , Inibidores da Topoisomerase I , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indenos/química , Indenos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Lactamas/química , Lactamas/farmacologia , Modelos Moleculares , Piridinas/química
18.
J Med Chem ; 50(18): 4419-30, 2007 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-17696418

RESUMO

The biological activity of indenoisoquinoline topoisomerase I (Top1) inhibitors can be greatly enhanced depending on the choice of substituents on the aromatic rings and lactam side chain. Previously, it was discovered that a 3-nitro group and a 9-methoxy group afforded enhanced biological activity. In the present investigation, indenoisoquinoline analogues were systematically prepared using combinations of nitro groups, methoxy groups, and hydrogen atoms in an effort to understand the contribution of each group toward cytotoxicity and Top1 inhibition. Analysis of the biological results suggests that the nitro group is important for Top1 inhibition and the methoxy group improves cytotoxicity. In addition, previously identified structure-activity relationships were utilized to select favorable lactam side chain functionalities for incorporation on the aromatic skeleton of analogues in this study. As a result, this investigation has provided optimal Top1 inhibitors equipotent to camptothecin that demonstrate low nanomolar cytotoxicities toward cancer cells.


Assuntos
Antineoplásicos/síntese química , Indenos/síntese química , Isoquinolinas/síntese química , Nitrocompostos/síntese química , Inibidores da Topoisomerase I , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Clivagem do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indenos/química , Indenos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Nitrocompostos/química , Nitrocompostos/farmacologia , Relação Estrutura-Atividade
19.
J Med Chem ; 50(18): 4388-404, 2007 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-17676830

RESUMO

Two series of indenoisoquinoline topoisomerase I inhibitors have been prepared to investigate optimal substituents on the indenone ring at the 9-position. The more exhaustive series was prepared using a nitrated isoquinoline ring that has been previously demonstrated to enhance biological activity. After preliminary biological evaluation, a more focused series of inhibitors was prepared utilizing a 2,3-dimethoxy-substituted isoquinoline ring. The results of the two series indicate the existence of superior functional groups such as methoxy, fluorine, and cyano for the indenoisoquinoline 9-position. Interestingly, these functional groups coincide with established structure-activity relationships for the 11-position of camptothecin.


Assuntos
Antineoplásicos/síntese química , Indenos/síntese química , Isoquinolinas/síntese química , Inibidores da Topoisomerase I , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Clivagem do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indenos/química , Indenos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
20.
Chem Commun (Camb) ; 53(49): 6597-6600, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28580477

RESUMO

A copper-mediated 11C-cyanation method employing arylboronic acids and [11C]HCN has been developed. This method was applied to the radiochemical synthesis of a wide range of aromatic 11C-nitriles in aqueous solutions. The use of readily accessible arylboronic acids as precursors makes this method complementary to the well-established 11C-cyanation methods that utilize aryl halide precursors.

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