RESUMO
We investigated the coordination properties of original macrocyclic Ln3+ complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd3+ complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media. The solution structure of the Ln3+ complex was unambiguously determined by a set of photophysical measurements and 1H, 13C, 89Y NMR data in combination with DFT calculations, which proved coordination of the heterocycle to Ln3+. The ability of the imidazothiadiazole moiety to sensitize Tb3+ luminescence was investigated. Finally, the relaxation properties were investigated by recording 1H nuclear magnetic relaxation dispersion (NMRD) profiles and 17O measurements. The water exchange rate is similar to that of GdDOTA as the less negative charge of the ligand is compensated for by the presence of a bulky heterocycle. Relaxivity is constant over a large range of pH values, demonstrating the favorable properties of the complex for imaging purposes.
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We present the in vitro characterisation of a Gd3+-based contrast agent that responds to Zn2+ upon interaction with Human Serum Albumin. We show that the contradictory in vivo behaviour is related to Gd3+-accumulation in Zn-rich tissues. This highlights the importance of the biodistribution of such contrast agents.
Assuntos
Meios de Contraste , Zinco , Humanos , Distribuição Tecidual , Imageamento por Ressonância MagnéticaRESUMO
Zn2+-responsive magnetic resonance imaging (MRI) contrast agents are typically composed of a Gd chelate conjugated to a Zn2+-binding moiety via a linker. They allow for Zn2+ detection in the presence of human serum albumin (HSA). In order to decipher the key parameters that drive their Zn2+-dependent MRI response, we designed a pyridine-based ligand, PyAmC2mDPA, and compared the properties of GdPyAmC2mDPA to those of analogue complexes with varying Gd core, Zn-binding moiety, or linker sizes. The stability constants determined by pH potentiometry showed the good selectivity of PyAmC2mDPA for Gd3+ (log KGd = 16.27) versus Zn2+ (log KZn = 13.58), proving that our modified Zn2+-binding DPA moiety prevents the formation of previously observed dimeric species. Paramagnetic relaxation enhancement measurements indicated at least three sites that are available for GdPyAmC2mDPA binding on HSA, as well as a 2-fold affinity increase when Zn2+ is present (KD = 170 µM versus KDZn = 60 µM). Fluorescence competition experiments provided evidence of the higher affinity for site II vs site I, as well as the importance of both the Zn-binding part and the Gd core in generating enhanced HSA affinity in the presence of Zn2+. Finally, an analysis of nuclear magnetic relaxation dispersion (NMRD) data suggested a significantly increased rigidity for the Zn2+-bound system, which is responsible for the Zn2+-dependent relaxivity response.
Assuntos
Gadolínio , Albumina Sérica Humana , Humanos , Gadolínio/química , Imageamento por Ressonância Magnética/métodos , Relação Estrutura-Atividade , Meios de Contraste/química , Quelantes/química , Zinco/químicaRESUMO
Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln3+) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic cleavage (L1) were also prepared. Proton Nuclear Magnetic Relaxation Dispersion (NMRD) profiles recorded on the gadolinium(III) (Gd3+) complexes, complemented with the assessment of hydration numbers via luminescence lifetime measurements on the Eu3+ analogues, allowed us to characterize the lanthanide coordination sphere in the chelates. These data suggest that the potential donor groups of the peptide side chains (carboxylate, amine) interfere in metal coordination, leading to non-hydrated LnL3 and LnL4 complexes. Nevertheless, GdL3 and GdL4 retain a relatively high relaxivity due to an important second-sphere contribution generated by the strongly hydrophilic peptide chain. Weak PARACEST effects are detected for the amine-derivative EuL1 and NdL1 chelates. Unfortunately, the GdL3 and GdL4 complexes are not significantly converted by the enzymes. The lack of enzymatic recognition of these complexes can likely be explained by the participation of donor groups from the peptide side chain in metal coordination.
Assuntos
Complexos de Coordenação/química , Elementos da Série dos Lantanídeos/química , Peptídeos/química , Fluorescência , Gadolínio/química , Ligantes , Espectroscopia de Prótons por Ressonância Magnética , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both Aß1-40 (Kd =4.4â nm) and amylin (Kd =4.5â nm), implicated, respectively in Alzheimer's disease and diabetes. The Scatchard analysis of surface plasmon resonance data obtained for a series of amphiphilic, PiB derivative GdL complexes indicate that their Aß1-40 or amylin binding affinity varies with their concentration, thus micellar aggregation state. The GdL chelates also affect peptide aggregation kinetics, as probed by thioflavin-T fluorescence assays. A 2D NMR study allowed identifying that the hydrophilic region of Aß1-40 is involved in the interaction between the monomer peptide and the Gd3+ complex. Finally, ex vivo biodistribution experiments were conducted in healthy mice by using 111 In labeled analogues. Their pancreatic uptake, â¼3 %ID g-1 , is promising to envisage amylin imaging in diabetic animals.
Assuntos
Complexos de Coordenação/química , Doença de Alzheimer , Amiloide , Peptídeos beta-Amiloides/metabolismo , Animais , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Camundongos , Fragmentos de Peptídeos/metabolismo , Distribuição TecidualRESUMO
Invited for the cover of this issue are Jean-Françoisâ Morfin and Évaâ Tóth at the CNRS in Orléans, and their collaborators from University of Debrecen, University of Coimbra and Université de Toulouse. The image depicts that when an amphiphilic compound is intravenously injected, monomer, pre-micellar and micellar forms can co-exist in the blood and have different affinities for amyloid peptides. Read the full text of the article at 10.1002/chem.202004000.
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Complexos de Coordenação/química , Amiloide , Polipeptídeo Amiloide das Ilhotas PancreáticasRESUMO
The photophysical properties of Eu3+ and Tb3+ complexes of DOTAGA and DO3A-monoamide conjugates of the Pittsburgh compound B (PiB) chromophore, prepared using linkers of different lengths and flexibilities, and which form stable negatively charged (LnL1), and uncharged (LnL2) complexes, respectively, were studied as potential probes for optical detection of amyloid aggregates. The phenylbenzothiazole (PiB) moiety absorbs light at wavelengths longer than 330 nm with a high molar absorption coefficient in both probes, and acts as an antenna in these systems. The presence of the luminescent Ln3+ ion quenches the excited states of PiB through an energy transfer process from the triplet state of PiB to the metal centre, and structured emission is seen from Eu3+ and Tb3+. The luminescence study indicates the presence of a 5D4 â T1 back transfer process in the Tb3+ complexes. It also provides insights on structural properties of the Eu3+ complexes, such as the high symmetry environment of the Eu3+ ion in a single macrocyclic conformation and the presence of one water molecule in its inner coordination sphere. The overall quantum yield of luminescence of EuL1 is higher than for EuL2. However, their low values reflect the low overall sensitization efficiency of the energy transfer process, which is a consequence of the large distances between the metal center and the antenna, especially in the EuL2 complex. DFT calculations confirmed that the most stable conformation of the Eu3+ complexes involves a combination of a square antiprismatic (SAP) geometry of the chelate and an extended conformation of the linker. The large calculated average distances between the metal center and the antenna point to the predominance of the Förster energy transfer mechanism, especially for EuL2. This study provides insights into the behavior of amyloid-targeted Ln3+ complexes as optical probes, and contributes towards their rational design.
Assuntos
Peptídeos beta-Amiloides/química , Compostos de Anilina/química , Quelantes/química , Elementos da Série dos Lantanídeos/química , Substâncias Luminescentes/química , Medições Luminescentes , Agregados Proteicos , Tiazóis/química , Teoria da Densidade Funcional , Humanos , Estrutura Molecular , Imagem Óptica , Processos FotoquímicosRESUMO
Many smart magnetic resonance imaging (MRI) probes provide response to a biomarker based on modulation of their rotational correlation time. The magnitude of such MRI signal changes is highly dependent on the magnetic field and the response decreases dramatically at high fields (>2â T). To overcome the loss of efficiency of responsive probes at high field, with fast-field cycling magnetic resonance imaging (FFC-MRI) we exploit field-dependent information rather than the absolute difference in the relaxation rate measured in the absence and in the presence of the biomarker at a given imaging field. We report here the application of fast field-cycling techniques combined with the use of a molecular probe for the detection of Zn2+ to achieve 166 % MRI signal enhancement at 3â T, whereas the same agent provides no detectable response using conventional MRI. This approach can be generalized to any biomarker provided the detection is based on variation of the rotational motion of the probe.
Assuntos
Complexos de Coordenação/química , Gadolínio/química , Zinco/análise , Biomarcadores/análise , Técnicas Biossensoriais/métodos , Complexos de Coordenação/síntese química , Campos Eletromagnéticos , Ligantes , Limite de Detecção , Imageamento por Ressonância Magnética/métodos , Sondas Moleculares/química , Albumina Sérica Humana/química , TermodinâmicaRESUMO
We propose quantitative assessment of zinc by combining nuclear and MR imaging. We use a cocktail of a Gd3+-complex providing a Zn2+-dependent MRI response and its 165Er3+ analogue allowing for concentration assessment. 165Er is readily obtained in a cyclotron and purified, which is indispensable for successful quantification of metal ions.
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Alzheimer's disease (AD) is a neurodegenerative disorder characterised by brain accumulation of toxic protein aggregates, including extracellular amyloid beta (Aß) plaques, inflammation, neuronal death and progressive cognitive dysfunction. Current diagnostic modalities, based on cognitive tests, fail to detect early AD onset, thus emphasising the need to develop improved methods for pre-symptomatic disease detection. Building on the properties of the Pittsburgh Compound B (PiB), an Aß-binding molecule suitable to use as positron emission tomography (PET) imaging agent, and aiming at using a more clinically available modality (like magnetic ressonance imaging, MRI), PiB derivatives have been conjugated to the macrocyclic chelator 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) monoamide. However, these derivatives do not readily cross the highly selective blood-brain barrier (BBB). Taking advantage of the capacity of functionalised carbon nanotubes (f-CNTs) to cross biological barriers, including the BBB, this manuscript reports on the conjugation of two PiB derivative Gd3+ complexes - Gd(L2) and Gd(L3) - to multi-walled f-CNTs (f-MWNTs) and assessment of their in vivo biodistribution and brain uptake. It is shown that Gd(L2) and Gd(L3) can be efficiently loaded onto different f-MWNTs, with significant improvement in brain accumulation of the conjugates compared to the free metal complexes. Overall, this study demonstrates that f-MWNTs have potential to be used as carriers in theranostic applications involving brain delivery of BBB impermeable compounds.
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AIM: Gadolinium-based nanoparticles were functionalized with either the Pittsburgh compound B or a nanobody (B10AP) in order to create multimodal tools for an early diagnosis of amyloidoses. MATERIALS & METHODS: The ability of the functionalized nanoparticles to target amyloid fibrils made of ß-amyloid peptide, amylin or Val30Met-mutated transthyretin formed in vitro or from pathological tissues was investigated by a range of spectroscopic and biophysics techniques including fluorescence microscopy. RESULTS: Nanoparticles functionalized by both probes efficiently interacted with the three types of amyloid fibrils, with KD values in 10 micromolar and 10 nanomolar range for, respectively, Pittsburgh compound B and B10AP nanoparticles. Moreover, they allowed the detection of amyloid deposits on pathological tissues. CONCLUSION: Such functionalized nanoparticles could represent promising flexible and multimodal imaging tools for the early diagnostic of amyloid diseases, in other words, Alzheimer's disease, Type 2 diabetes mellitus and the familial amyloidotic polyneuropathy.
Assuntos
Compostos de Anilina/química , Gadolínio/química , Nanopartículas/química , Placa Amiloide/diagnóstico , Anticorpos de Domínio Único/química , Tiazóis/química , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/análise , Animais , Encéfalo/patologia , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Imuno-Histoquímica , Polipeptídeo Amiloide das Ilhotas Pancreáticas/análise , Camundongos , Imagem MultimodalRESUMO
BACKGROUND: Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-ß structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients' treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [(11)C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimally-invasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Aß amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Aß(1-42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils. RESULTS: The results of surface plasmon resonance studies showed that both functionalized nanoparticles interact with Aß(1-42) fibrils with equilibrium dissociation constant (Kd) values of 403 and 350 µM respectively, whilst they did not interact with V30M-TTR fibrils. Similar experiments, performed with PIB, displayed an interaction both with Aß(1-42) fibrils and V30M-TTR fibrils, with Kd values of 6 and 10 µM respectively, confirming this agent as a general amyloid fibril marker. Thereafter, the ability of functionalized nanoparticle to target and bind selectively Aß aggregates was further investigated by immunohistochemistry on AD like-neuropathology brain tissue. Pictures clearly indicated that KLVFF-grafted or LPFFD-grafted to AGuIX nanoparticle recognized and bound the Aß amyloid plaque localized in the mouse hippocampus. CONCLUSION: These results constitute a first step for considering these functionalized nanoparticles as a valuable multimodal imaging tool to selectively discriminate and diagnose amyloidoses.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/química , Gadolínio/química , Hipocampo/metabolismo , Nanopartículas Metálicas/química , Fragmentos de Peptídeos/química , Placa Amiloide/diagnóstico por imagem , Pré-Albumina/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hipocampo/ultraestrutura , Humanos , Cinética , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Mutação , Fragmentos de Peptídeos/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Pré-Albumina/metabolismo , Ligação Proteica , Ressonância de Plasmônio de SuperfícieRESUMO
PURPOSE: The aim of this work is to develop an efficient and fully automated radiosynthesis of three derivatives of the Pittsburgh compound B labeled with gallium-68 for the detection of amyloid plaques. PROCEDURES: The radiolabeling of the precursors and purification of the radiolabeled agents by high pressure liquid chromatography has been studied prior to their in vitro and in vivo evaluations. RESULTS: The complete process led, in 50 min, to pure Ga-68 products in a 12-38 % yield and with appreciable specific radioactivity (SRA, 85-168 GBq/µmol) which enabled us to demonstrate a considerable in vivo stability of the products. Unfortunately, this result was associated with a poor blood-brain barrier (BBB) permeability and a limited uptake of our compounds by amyloid deposits was observed by in vitro autoradiography. CONCLUSION: Although we have not yet identified a compound able to significantly mark cerebral amyloidosis, this present investigation will likely contribute to the development of more successful Ga-68 radiotracers.
Assuntos
Compostos de Anilina/química , Radioisótopos de Gálio/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Tiazóis/química , Animais , Autorradiografia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição TecidualRESUMO
We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature (17)O NMR and NMRD study allowed the assessment of the water exchange rate, k ex (298) = 9.7 × 10(6) s(-1), about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd(3+) centers as evidenced by higher relaxivities at 20-60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Aß1-40 [K d = 194 ± 11 µM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 ± 68 M(-1) for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Aß1-40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Aß1-40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the α-helix and ß-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils.
Assuntos
Peptídeos beta-Amiloides/química , Compostos Heterocíclicos/química , Compostos Organometálicos/química , Espectroscopia de Ressonância MagnéticaRESUMO
Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Aß1-40 peptide. We have studied lanthanide(III) chelates of two PiB-derivative ligands (PiB=Pittsburgh compound B), L(1) and L(2), differing in the length of the spacer between the metal-complexing DO3A macrocycle (DO3A=1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and the peptide-recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Aß1-40 (KD =67-160â µM), primarily through the benzothiazole unit. HSQCâ NMR spectroscopy on the (15) N-labeled, monomer Aß1-40 peptide indicates nonsignificant interaction with monomeric Aß. Time-dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Aß1-40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Aß fibril formation distinctly. Whereas GdL(1), at higher concentrations, stabilizes ß-sheets, GdL(2) prevents aggregation by promoting α-helical structures. These results give insight into the behavior of amyloid-targeted metal complexes in general and contribute to a more rational design of metal-based diagnostic and therapeutic agents for amyloid- associated pathologies.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Compostos de Anilina/metabolismo , Complexos de Coordenação/metabolismo , Elementos da Série dos Lantanídeos/metabolismo , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/ultraestrutura , Agregados Proteicos , Tiazóis/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Compostos de Anilina/química , Complexos de Coordenação/química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Elementos da Série dos Lantanídeos/química , Espectroscopia de Ressonância Magnética , Ressonância de Plasmônio de Superfície , Tiazóis/químicaRESUMO
A series of novel pyridine-based Gd(3+) complexes have been prepared and studied as potential MRI contrast agents for Zn(2+) detection. By independent assessment of molecular parameters affecting relaxivity, we could interpret the relaxivity changes observed upon Zn(2+) binding in terms of variations of the rotational motion.
Assuntos
Meios de Contraste/síntese química , Gadolínio/química , Imageamento por Ressonância Magnética , Zinco/análise , Meios de Contraste/química , Estabilidade de Medicamentos , Corantes Fluorescentes/química , Ligantes , Modelos Moleculares , Zinco/químicaRESUMO
In an effort towards the visualization of ß-amyloid (Aß) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer's disease, we report the synthesis and characterization of stable, noncharged Gd(3+) complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aß plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol-water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00-1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined (17)O NMR and (1)H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari-Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Aß1-40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with KA values ranging between 250 and 910 M(-1).
Assuntos
Compostos de Anilina/química , Gadolínio/química , Imageamento por Ressonância Magnética/métodos , Compostos Organometálicos/química , Placa Amiloide/diagnóstico , Tiazóis/química , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Micelas , Compostos Organometálicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Permeabilidade , Albumina Sérica/metabolismo , Água/químicaRESUMO
In an effort toward the visualization of ß-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a well-established marker of Aß plaques, to DO3A-monoamide that is capable of forming stable, noncharged complexes with different trivalent metal ions including Gd(3+) for MRI and (111)In(3+) for SPECT applications. Proton relaxivity measurements evidenced binding of Gd(DO3A-PiB) to the amyloid peptide Aß1-40 and to human serum albumin, resulting in a two- and four-fold relaxivity increase, respectively. Ex vivo immunohistochemical studies showed that the DO3A-PiB complexes selectively target Aß plaques on Alzheimer's disease human brain tissue. Ex vivo biodistribution data obtained for the (111)In-analogue pointed to a moderate blood-brain barrier (BBB) penetration in adult male Swiss mice (without amyloid deposits) with 0.36% ID/g in the cortex at 2 min postinjection.
RESUMO
The syntheses of a new cyclen-based ligand L(2) containing four N-[2-(2-hydroxyethoxy)ethyl]acetamide pendant arms and of its lanthanide(III) complexes [LnL(2)(H(2)O)]Cl(3) (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln(III) complexes of a previously reported analogue L(1) in which two opposite amide arms have been replaced by coordinating pyridyl units. The structure and dynamics of the La(III), Lu(III), and Yb(III) complexes in solution were studied by using multinuclear NMR investigations and density functional theory calculations. Luminescence lifetime measurements in H(2)O and D(2)O solutions of the [Ln(L(2))(H(2)O)](3+) complexes (Ln = Eu or Tb) were used to investigate the number of H(2)O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H(2)O molecule in a buffered aqueous solution. Fluoride binding to the latter complexes was investigated using a combination of absorption spectroscopy and steady-state and time-resolved luminescence spectroscopy, pointing to a surprisingly weak interaction in the case of L(2) (log K = 1.4 ± 0.1). In contrast to the results in solution, the X-ray crystal structure of the lanthanide complex showed the ninth coordination position occupied by a chloride anion. In the case of L(1), the X-ray structure of the [(EuL(1))(2)F] complex features a bridging fluoride donor with an uncommon linear Eu-F-Eu entity connecting two almost identical [Eu(L(1))](3+) units. Encapsulation of the F(-) anion within the two complexes is assisted by π-π stacking between the pyridyl rings of two complexes and C-H···F hydrogen-bonding interactions involving the anion and the pyridyl units.
Assuntos
Fluoretos , Elementos da Série dos Lantanídeos/química , Compostos Organometálicos/síntese química , Acetamidas/química , Soluções Tampão , Técnicas de Química Analítica , Cristalografia por Raios X , Ciclamos , Óxido de Deutério/química , Fluoretos/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos com 1 Anel/química , Ligantes , Luminescência , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Piridinas/química , Teoria Quântica , Soluções , Água/química , Espectroscopia por Absorção de Raios XRESUMO
Gallium complexes are gaining increasing importance in biomedical imaging thanks to the practical advantages of the (68)Ga isotope in Positron Emission Tomography (PET) applications. (68)Ga has a short half-time (t(1/2) = 68 min); thus the (68)Ga complexes have to be prepared in a limited time frame. The acceleration of the formation reaction of gallium complexes with macrocyclic ligands for application in PET imaging represents a significant coordination chemistry challenge. Here we report a detailed kinetic study of the formation reaction of the highly stable Ga(NOTA) from the weak citrate complex (H(3)NOTA = 1,4,7-triazacyclononane-1,4,7- triacetic acid). The transmetalation has been studied using (71)Ga NMR over a large pH range (pH = 2.01-6.00). The formation of Ga(NOTA) is a two-step process. First, a monoprotonated intermediate containing coordinated citrate, GaHNOTA(citrate)*, forms in a rapid equilibrium step. The rate-determining step of the reaction is the deprotonation and slow rearrangement of the intermediate accompanied by the citrate release. The observed reaction rate shows an unusual pH dependency with a minimum at pH 5.17. In contrast to the typical formation reactions of poly(amino carboxylate) complexes, the Ga(NOTA) formation from the weak citrate complex becomes considerably faster with increasing proton concentration below pH 5.17. We explain this unexpected tendency by the role of protons in the decomposition of the GaHNOTA(citrate)* intermediate which proceeds via the protonation of the coordinated citrate ion and its subsequent decoordination to yield the final product Ga(NOTA). The stability constant of this intermediate, log K(GaHNOTA(citrate)*) = 15.6, is remarkably high compared to the corresponding values reported for the formation of macrocyclic lanthanide(III)-poly(amino carboxylates). These kinetic data do not only give mechanistic insight into the formation reaction of Ga(NOTA), but might also contribute to establish optimal experimental conditions for the rapid preparation of Ga(NOTA)-based radiopharmaceuticals for PET applications.