Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.000
Filtrar
1.
J Med Chem ; 63(9): 4496-4505, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302130

RESUMO

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
2.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
3.
Org Biomol Chem ; 18(16): 3104-3116, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32253415

RESUMO

Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1-40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq µmol-1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.


Assuntos
Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Receptores da Família Eph/análise , Xantinas/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Efrina-A2/análise , Humanos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Imagem Molecular/métodos , Ratos , Receptor EphB4/análise , Receptores da Família Eph/antagonistas & inibidores
4.
Nat Commun ; 11(1): 1736, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269227

RESUMO

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.


Assuntos
Radioisótopos de Carbono/química , Fluoretos/química , Compostos de Organossilício/química , Acetoacetatos/química , Metilação , Racloprida/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
5.
Dalton Trans ; 49(15): 4732-4740, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32207493

RESUMO

Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic ß-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of ß-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in ß-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(iii) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in ß-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]-, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of ß-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.


Assuntos
Meios de Contraste/química , Complexos de Coordenação/química , Exenatida/química , Gadolínio/química , Células Secretoras de Insulina/patologia , Imagem por Ressonância Magnética , Pâncreas/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Animais , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química
6.
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
7.
J Med Chem ; 63(4): 1717-1723, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32026684

RESUMO

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I- in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Purinas/farmacologia , Compostos Radiofarmacêuticos , Simportadores/metabolismo , Animais , Iodetos/metabolismo , Radioisótopos do Iodo/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons , Purinas/síntese química , Purinas/química , Purinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Simportadores/genética
8.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041321

RESUMO

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3'- and 2'-fluorinated ProTides following different radiosynthetic approaches. The 3'-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15-30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/µmol (total synthesis time of 130 min.). The 2'-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1-5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/µmol (total synthesis time of 240 min).


Assuntos
Radioisótopos de Flúor/química , Nucleotídeos/síntese química , Compostos Radiofarmacêuticos/síntese química , Halogenação , Tomografia por Emissão de Pósitrons/métodos , Radioquímica/métodos
9.
Org Biomol Chem ; 18(13): 2387-2391, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32073113

RESUMO

Dihydromethidine (DHM) labeled with 18F at the para position of the peripheral benzene ring was designed as a positron emission tomography (PET) radiotracer for non-invasive imaging of reactive oxygen species (ROS). This compound readily crosses the blood-brain barrier and is oxidized by ROS, and the oxidation product is retained intracellularly. PET imaging of ROS-producing rat brain microinfused with sodium nitroprusside identified specific brain regions with high ROS concentrations. This tracer should be useful for studies of the pathophysiological roles of ROS, and in the diagnosis of neurodegenerative diseases.


Assuntos
Encéfalo/diagnóstico por imagem , Fenantridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Radioisótopos de Flúor/química , Inflamação/induzido quimicamente , Inflamação/diagnóstico por imagem , Inflamação/patologia , Nitroprussiato , Oxirredução , Fenantridinas/síntese química , Fenantridinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos
10.
J Med Chem ; 63(6): 3381-3389, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32081008

RESUMO

We have synthesized and characterized [18F]-N-(4-chloro-3-((fluoromethyl-d2)thio)phenyl)-picolinamide ([18F]15) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [18F]15 displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps. The radiochemical yield of [18F]15 was 11.6 ± 2.9% (n = 7, decay corrected) with a purity of 99% and a molar activity of 84.1 ± 11.8 GBq/µmol. Ex vivo biodistribution studies showed reversible binding of [18F]15 in all investigated tissues including the brain, liver, heart, lungs, and kidneys. PET imaging studies in male Sprague Dawley rats showed that [18F]15 accumulates in the brain regions known to express mGluR4. Pretreatment with the unlabeled mGluR4 PAM compounds 13 (methylthio analogue) and 15 showed significant dose-dependent blocking effects. These results suggest that [18F]15 is a promising radioligand for PET imaging mGluR4 in the brain.


Assuntos
Picolinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Glutamato Metabotrópico/análise , Animais , Encéfalo/metabolismo , Estabilidade de Medicamentos , Radioisótopos de Flúor/química , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Picolinas/síntese química , Picolinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo
11.
Chem Commun (Camb) ; 56(16): 2507-2510, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32003763

RESUMO

Radiolabeling of peptides with fluorine-18 is hurdled by their chemical sensitivity and complicated processes. Original triflyl-pyridine intermediates afforded ammonium precursors that were radiolabeled at low temperature. From that study, a generic tag has been designed to allow a simple one-step/late-stage radiolabelling of peptides. The strategy has been transposed to an automated "on-resin" radiolabelling.


Assuntos
Peptídeos/síntese química , Compostos Radiofarmacêuticos/síntese química , Resinas Sintéticas/síntese química , Radioisótopos de Flúor , Halogenação , Estrutura Molecular , Peptídeos/química , Compostos Radiofarmacêuticos/química , Resinas Sintéticas/química , Temperatura
12.
Eur J Med Chem ; 188: 112032, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926467

RESUMO

Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Hidrazinas/química , Niacinamida/análogos & derivados , Compostos de Organotecnécio/química , Piperazinas/química , Piridinas/química , Compostos Radiofarmacêuticos/química , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/farmacologia , Células MCF-7 , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Relação Estrutura-Atividade , Distribuição Tecidual
13.
Inorg Chem ; 59(3): 1985-1995, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31976659

RESUMO

44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H-13C HSQC, 1H-13C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)]- presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)]- was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)]- (24.7) and [Sc(DOTA)]- (23.9). In radiolabeling, [44Sc][Sc(pypa)]- formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H4pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Neoplasias Experimentais/diagnóstico por imagem , Antígeno Prostático Específico/análise , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Escândio/química , Termodinâmica , Animais , Quelantes/síntese química , Quelantes/farmacocinética , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Teoria da Densidade Funcional , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Escândio/farmacocinética , Distribuição Tecidual
14.
Chemistry ; 26(9): 1989-2001, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31755596

RESUMO

Bifunctional chelators as parts of modular metal-based radiopharmaceuticals are responsible for stable complexation of the radiometal ion and for covalent linkage between the complex and the targeting vector. To avoid loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups. The C9 position of the very stable CuII chelator 3,7-diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisation does not disturb the metal binding centre. We describe the preparation and characterisation of a set of novel bispidine derivatives equipped with suitable functional groups for diverse bioconjugation reactions, including common amine coupling strategies (bispidine-isothiocyanate) and the Cu-free strain-promoted alkyne-azide cycloaddition. We demonstrate their functionality and versatility in an exemplary way by conjugation to an antibody-based biomolecule and validate the obtained conjugate in vitro and in vivo.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Quelantes/química , Cobre/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Linhagem Celular Tumoral , Cetuximab/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Reação de Cicloadição , Humanos , Camundongos , Microscopia de Fluorescência , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Transplante Heterólogo
15.
Chem Commun (Camb) ; 56(3): 415-418, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821393

RESUMO

We report a novel 1,2-catechol based radioiodinated precursor for radioiodination of bicyclo[6.1.0]nonyne (BCN) installed biologically active molecules using a strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition reaction (SPOCQ) under ambient conditions. Compared to the reported methodologies, the new strategy demonstrates some clear advantages, including high in vitro and in vivo stability, high radiochemical yield, and exceptionally fast reaction kinetics at micro-molar concentration.


Assuntos
Reação de Cicloadição , Quinonas/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Catecóis/química , Coração/diagnóstico por imagem , Radioisótopos do Iodo/química , Marcação por Isótopo , Cinética , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
16.
J Med Chem ; 63(2): 747-755, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31846326

RESUMO

Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it is generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed with respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.


Assuntos
Radioisótopos de Flúor/química , Galectina 3/antagonistas & inibidores , Glucose/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Animais , Feminino , Glucose/análogos & derivados , Glucose/síntese química , Meia-Vida , Marcação por Isótopo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Long-Evans , Distribuição Tecidual
17.
Eur J Med Chem ; 187: 111979, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877537

RESUMO

Fluorine-18 is one of the most widely used radionuclides for the production of radiopharmaceuticals for positron emission tomography (PET). The radiolabeling methods like nucleophilic, electrophilic, Cu mediated mechanisms or prosthetic groups are widely using to achieve high regioselective radiochemical yields. It acts as a powerful tool to identify new drug targets through cellular uptake, pharmacokinetic (ADME) and pharmacodynamic parameters of the 18F labeled tracer or drug. These PET tracers have been developed based on the receptors expressed in a disease condition. A number of 18F radiotracers have been developed against the Tropomyosin Receptor Kinases (Trks), Carbonic anhydrases (CAs), Epidermal Growth Factor Receptors (EGFR), Poly ADP ribose polymerase (PARP) etc. for the diagnosis in cancer therapy. The current research also focused on the development of novel 18F radiotracers for neurological conditions for deciphering underlying physiology in diseases like Alzheimer, and Parkinson. Therefore, in this review we have focused on 18F labeling methods, and radiotracers developed against common cancers and neurological conditions.


Assuntos
Inibidores Enzimáticos/química , Neoplasias/diagnóstico por imagem , Doenças do Sistema Nervoso/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Animais , Anidrases Carbônicas/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Radioisótopos de Flúor , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo
18.
Contrast Media Mol Imaging ; 2019: 1760184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787861

RESUMO

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Radioisótopos de Carbono , Indazóis , Proteínas de Neoplasias/análise , Fosfatidilinositol 3-Quinases/análise , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Sulfonamidas , Animais , Neoplasias da Mama/patologia , Radioisótopos de Carbono/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Eliminação Hepatobiliar , Xenoenxertos , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Indazóis/farmacologia , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Transplante de Neoplasias , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Transdução de Sinais , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Distribuição Tecidual
19.
J Am Chem Soc ; 141(49): 19404-19414, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31794205

RESUMO

A major chemical challenge facing implementation of 225Ac in targeted alpha therapy-an emerging technology that has potential for treatment of disease-is identifying an 225Ac chelator that is compatible with in vivo applications. It is unclear how to tailor a chelator for Ac binding because Ac coordination chemistry is poorly defined. Most Ac chemistry is inferred from radiochemical experiments carried out on microscopic scales. Of the few Ac compounds that have been characterized spectroscopically, success has only been reported for simple inorganic ligands. Toward advancing understanding in Ac chelation chemistry, we have developed a method for characterizing Ac complexes that contain highly complex chelating agents using small quantities (µg) of 227Ac. We successfully characterized the chelation of Ac3+ by DOTP8- using EXAFS, NMR, and DFT techniques. To develop confidence and credibility in the Ac results, comparisons with +3 cations (Am, Cm, and La) that could be handled on the mg scale were carried out. We discovered that all M3+ cations (M = Ac, Am, Cm, La) were completely encapsulated within the binding pocket of the DOTP8- macrocycle. The computational results highlighted the stability of the M(DOTP)5- complexes.


Assuntos
Actínio/química , Amerício/química , Quelantes/química , Complexos de Coordenação/síntese química , Cúrio/química , Lantânio/química , Compostos Organofosforados/química , Compostos Radiofarmacêuticos/síntese química , Complexos de Coordenação/química , Ligantes , Estrutura Molecular , Compostos Radiofarmacêuticos/química
20.
Sci Rep ; 9(1): 19299, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848442

RESUMO

Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [18F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine (123,125I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [18F]ICMT11 (Ki = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/isolamento & purificação , Radioisótopos do Iodo/farmacologia , Neoplasias/diagnóstico por imagem , Animais , Apoptose/genética , Caspase 3/química , Caspase 3/genética , Linhagem Celular Tumoral , Cobre/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia , Xenoenxertos , Humanos , Radioisótopos do Iodo/química , Isatina/síntese química , Isatina/farmacologia , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Triazóis/síntese química , Triazóis/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA