Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
1.
Molecules ; 28(2)2023 Jan 13.
Article in English | MEDLINE | ID: mdl-36677878

ABSTRACT

With the objective to develop a potential 99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with 99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to 99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells.


Subject(s)
Flutamide , Receptors, Androgen , Male , Humans , Flutamide/pharmacology , Diagnostic Imaging , Radiopharmaceuticals/chemistry , Technetium/chemistry , Organotechnetium Compounds/chemistry
2.
Chem Biol Drug Des ; 101(3): 593-604, 2023 03.
Article in English | MEDLINE | ID: mdl-36138520

ABSTRACT

Opportunistic infections are a problem of great relevance in public health and the precise detection and localization of infection in the early stages of the disease is of great importance for patient management as well as cost containment. Our proposal seeks to contribute to developing a new agent that meets the needs of diagnosis and follow-up of fungal and bacterial infections, focused on the design of a radiotracer with the potential for recognition of hidden infection foci. Defensins are plant antimicrobial peptides that not only show activity against plant pathogens but also against human ones. A short analogue of EcgDf1 defensin, EcgDf21d (NH2 -ERFTGGHCRGFRRRCFCTKHC-COOH), was labelled through the formation of a 99m Tc-HYNIC complex which was assessed for physicochemical and biological behaviour both in vitro and in vivo. The [99m Tc]Tc-HYNIC-EcgDf21 labelling procedure rendered a single product with remarkably high RCP and stability in the labelling milieu. The Log p value indicated that [99m Tc]Tc-HYNIC-EcgDf21 has a hydrophilic behaviour, confirmed by the biodistribution profiles. The optimal uptake value was obtained for Candida albicans infection model reaching a lesion/muscle ratio of 3, this correlates with in vitro binding studies, and the lesion can be definitely observed in the scintigraphic images.


Subject(s)
Bacterial Infections , Candidiasis , Humans , Bacterial Infections/diagnostic imaging , Defensins , Radionuclide Imaging , Technetium , Tissue Distribution
3.
Chem Biol Drug Des ; 98(1): 182-191, 2021 07.
Article in English | MEDLINE | ID: mdl-33982434

ABSTRACT

In vivo receptor targeting with radiolabelled peptide-based probes is an attractive approach for the development of novel radiotracers for molecular imaging. This work presents the development and characterization of two novel neuropeptide Y analogues labelled with a positron emitter 68 Ga, for potential use in breast cancer imaging. Both analogues share the same amino acid sequence and were derivatized with NOTA through either a lysine linker (L1) or an acetylated lysine (L2). In both cases, a single product with radiochemical purity higher than 95% was obtained. The two complexes were hydrophilic, showed remarkable in vitro stability, good cellular uptake, binding affinity in the nanomolar range and high cellular internalization rate. Biodistribution studies revealed low blood uptake and elimination through the urinary tract. The addition of an acetyl group in the spacer increased the lipophilicity of C2 and modified the reactivity of the ε-amino group of the lysine which resulted in lower protein binding and lower percentage of injected dose in bladder and urine. The tumour versus muscle ratio was (3.8 ± 0.4) for 68 Ga-L1 and (4.7 ± 0.4) for 68 Ga-L2. These results encourage performing further studies in order to complete the evaluation of both tracers as potential radiopharmaceutical for breast cancer imaging.


Subject(s)
Breast Neoplasms/diagnostic imaging , Gallium Radioisotopes/chemistry , Neuropeptide Y/chemistry , Radiopharmaceuticals/chemistry , Amines/chemistry , Amino Acid Sequence , Animals , Biological Transport , Cineradiography , Female , Humans , Lysine/chemistry , Mice, Nude , Neoplasms, Experimental , Neuropeptide Y/blood , Neuropeptide Y/pharmacokinetics , Neuropeptide Y/urine , Protein Binding , Radiopharmaceuticals/blood , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/urine , Staining and Labeling , Structure-Activity Relationship , Tissue Distribution
4.
Chem Biol Drug Des ; 95(2): 302-310, 2020 02.
Article in English | MEDLINE | ID: mdl-31709766

ABSTRACT

The aim of this work was to develop and evaluate a 99m Tc-labeled neuropeptide Y derivative with affinity toward Y1-receptor. The selected amino acid sequence included nine amino acids derived from the C-terminal portion of the NPY complemented with the addition of one cysteine-mercaptoacetic acid moiety to bind the radiometal. Labeling was achieved through the preparation of a 3 + 1 nitrido complex. Physicochemical evaluation, cell uptake, internalization and externalization studies, and competitive assays were performed. Biodistribution experiments were carried out in normal and tumor-bearing mice. A single product with radiochemical purity >90% and high stability was obtained. In vitro analysis showed specific cellular uptake, IC50 of 73.2 nM, and a high internalization rate (80%). Biodistribution studies showed low blood and renal uptake and combined hepatobiliary and urinary elimination. Preliminary studies in mice bearing induced breast tumors rendered promising uptake values.


Subject(s)
Breast Neoplasms/diagnostic imaging , Neuropeptide Y/administration & dosage , Radiopharmaceuticals/administration & dosage , Technetium/administration & dosage , Animals , Cell Line, Tumor , Humans , Mice , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution
5.
Curr Radiopharm ; 9(2): 137-42, 2016.
Article in English | MEDLINE | ID: mdl-26876366

ABSTRACT

BACKGROUND AND OBJECTIVE: The design of target-specific molecular imaging probes to determine infection sites are mainly based on the biochemistry of the inflammatory response that may lead to an ideal agent for infection imaging. Infectious diseases timely and specifically diagnosed can be clinically challenging but essential for the patient's recovery. Laboratory tests can detect the responsible microorganism but cannot discriminate between sterile inflammatory disease and truly infectious disease. On the other hand, scintigraphic images, can pinpoint the infection in the body. METHODS: Bacteriophages (phages) are viruses that infect specific bacterial strains. Given the composition of the protein capsid, they could be used as radiopharmaceuticals to diagnose bacterial infection. In this case, PP7 phage was labelled and evaluated as a specific tracer for Pseudomonas aeruginosa infections. 99mTc-Phage synthesis used HYNIC as a bifunctional agent. Physicochemical evaluation included studies such as stability in time, ligand exchange, lipophilicity and bacterial binding assay. Three groups of animals namely; healthy, infected with Pseudomonas aeruginosa and induced sterile inflammation were used to conduct biological evaluation Results: The radiolabelling process required size exclusion purification of the 99mTc-Phage, which was obtained with a radiochemical purity higher than 90%, during 18 hours post labelling. The collective accumulation in the stomach, small intestine and large intestine and thyroid of 99mTc-Phage was negligible, indicating no in vivo reoxidation. The complex presented urinary elimination. Target/ non-target ratio (T/NT) was determined both for sterile inflammation and for infection. Values were 2.5 ± 0.4 and 4.2 ± 0.3 respectively. These values indicate significant differences between sterile inflammation and infection by Pseudomonas aeruginosa (p<0.05 unpaired two sided t-test). CONCLUSION: Targeted biodistribution profile and good T/NT ratios, indicate that this complex presents enough specificity to discriminate between infection caused by Pseudomonas aeruginosa and sterile inflammation.


Subject(s)
Bacteriophages , Pseudomonas Infections/diagnosis , Radiopharmaceuticals/pharmacokinetics , Technetium , Animals , Female , Mice , Tissue Distribution
6.
Rev. med. nucl. Alasbimn j ; 14(54)oct. 2011. ilus, tab, graf
Article in Spanish | LILACS | ID: lil-609894

ABSTRACT

El avance del HIV ha favorecido el aumento de infecciones fúngicas como candidiasis y aspergilosis invasivas. Varias clases de antifúngicos son utilizados para el tratamiento de las mismas y éstos pueden ser radiomarcados con un agente emisor gamma que permita la detección mediante centellografia de focos de infección. El Voriconazol es un triazol adecuado para la marcación mediante la formación de un complejo unido al precursor [99mTc(H2O)3(CO)3]+. El objetivo fue marcar y determinar las características fisicoquímicas y biológicas del voriconazol con 99mTc para la detección temprana de infecciones. La pureza radioquímica se determinó por HPLC y permitió establecer que el complejo permanece estable durante al menos 120 min. Los estudios in vivo en modelos de inflamación estéril, infección con C. Albicans y A. Niger mostraron diferenciación de los procesos tanto en biodistribución como en imágenes centellográficas.


The spread of HIV has led to an increase of fungal infections such as candidiasis and invasive aspergillosis. Several types of antifungals are used to treat them and some of them can be radiolabeled with a gamma emitting agent to allow detection by scintigraphy of foci of infection. Voriconazole is a triazole agent, suitable for the synthesis of a complex linked with the precursor [99mTc(H2O)3(CO)3]+. The aim of his work was to label and determine the physicochemical and biological characteristics of voriconazole with 99mTc for the early detection of fungal infections. Radiochemical purity was determined by HPLC and the complex remained stable during at least 120 min. In vivo studies in rats bearing either sterile inflammation, infection with C. Albicans or A. Niger showed differentiation of the processes not only in biosdistribution but also in scintigraphic images.


Subject(s)
Humans , Animals , Rats , Antifungal Agents , Aspergillosis , Candidiasis , Pyrimidines , Technetium , Triazoles , Antifungal Agents/pharmacokinetics , Tissue Distribution , Drug Stability , Time Factors , Immunocompromised Host , HIV Infections/complications , Mycoses , Models, Biological , Pyrimidines/pharmacokinetics , Radiopharmaceuticals , Technetium/pharmacokinetics , Triazoles/pharmacokinetics
7.
Nucl Med Biol ; 38(2): 279-85, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21315284

ABSTRACT

INTRODUCTION: There are many diseases associated with variations in the expression of apoptosis such as organ rejection after transplantation, myocardial ischemia or infarct and neurodegenerative diseases. For this reason, the early visualization of this process is relevant to set fast and effective therapeutic strategies. METHODS: The precursor was prepared according to the procedure reported by R. Alberto, R. Schibli, P. Schubiger, U. Abram, and T. Kaden [Reactions with the technetium and rhenium carbonyl complexes (NEt(4))[MX(3)(CO)(3)]. Synthesis and structure of Tc(CN-But)(3)(CO)(3)](NO(3)) and (Net(4))[Tc(2)(µ-SCH(2)CH(2)OH)(3)(CO)(3)], Polyhedron 1996;15: 1079-89]. Recombinant annexin V was incubated with [(99m)Tc](H(2)O)3(CO)(3)(+) solution, previously neutralized with buffer. Biodistribution studies were performed in 8-week-old female Wistar rats. Animals were housed and treated in compliance with institutional guidelines related to animal experimentation. Work protocol was previously approved by the Animal Ethics Committee of the university. Two groups of rats were defined. One was used as control and the other group was previously injected with 150 mg/kg ip of cyclophosphamide to induce apoptosis. RESULTS: The synthesis of carbonyl precursor achieved yields higher than 90%, and the radiolabeled protein was obtained with 92% of radiochemical purity and high stability in vitro. An important uptake in apoptotic tissues was confirmed by biodistributions, scintigraphic images and histological studies. CONCLUSIONS: Biodistribution studies revealed hepatobiliary elimination, high stability in vivo and important uptake in the reticuloendothelial system. In the pathologic model, higher uptake values correspond to the liver, spleen, lungs and femur. Histological studies confirmed the development of apoptosis at 8 and 24 h postinduction in the spleen and lymphocyte bulks in the peribronchial area. Scintigraphic images confirmed high uptake both the spleen and the lungs.


Subject(s)
Annexin A5 , Apoptosis , Organotechnetium Compounds , Recombinant Proteins , Animals , Annexin A5/chemistry , Annexin A5/pharmacokinetics , Chemical Phenomena , Drug Stability , Female , Humans , Models, Animal , Rats , Rats, Wistar , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics
9.
BMC Nucl Med ; 5: 5, 2005 Oct 18.
Article in English | MEDLINE | ID: mdl-16232323

ABSTRACT

BACKGROUND: Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery. METHODS: In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, (99mTc-DTPA) and (99mTc-MDP), and two lipophilic tracers, (99mTc-ECD) and (99mTc-MIBI), were used as drug models. RESULTS: Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for 99mTc-DTPA, 99mTc-ECD and 99mTc-MIBI. High correlation coefficients were found for 99mTc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies. CONCLUSION: Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics.

10.
Eur J Pharm Biopharm ; 57(2): 347-52, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15018995

ABSTRACT

Tablets containing drugs of different lipophilicity, ranitidine and cinarizine, and placebo were prepared and their in vitro behaviour was studied by dissolution and disintegration tests. [(99m)Tc]Diethylenetriamine-pentaacetic acid ([(99m)Tc]DTPA) and [(99m)Tc]ethyl cysteinate dimer ([(99m)Tc]ECD) were used as tracers of the process. Both of them were added to tablets during wet granulation. Dissolution and disintegration profiles were assessed at different pH values (1, 4 and 7). Radioactivity was evaluated in filtered samples and scintigraphic studies were carried out in gamma camera. Stability in dissolution media was confirmed for both tracers under these conditions. Dissolution and disintegration velocity constants were calculated. [(99m)Tc]DTPA proved to be an appropriate tracer for polar drugs such as ranitidine. Nevertheless, it was not a suitable tracer for lipophilic active drugs such as cinarizine. On the other hand, the most lipophilic tracer, [(99m)Tc]ECD, exhibited the opposite behaviour. Scintigraphic studies of the disintegration process did not show significant differences between placebos and tablets containing active drugs. As disintegration is a physical process it does not discriminate between chemical differences in tablet formulations. Both methods complement each other because the dissolution process can be followed when a suitable radiotracer is chosen according to the physicochemical characteristics of the active drug.


Subject(s)
Cysteine/analogs & derivatives , Cysteine/chemistry , Drug Delivery Systems/methods , Pentetic Acid/chemistry , Radiopharmaceuticals/chemistry , Technetium/chemistry , Cysteine/metabolism , Pentetic Acid/metabolism , Radiopharmaceuticals/metabolism , Solubility , Technetium/metabolism
11.
Acta farm. bonaer ; 19(3): 217-24, jun.-sept. 2000. ilus, tab
Article in Spanish | BINACIS | ID: bin-9959

ABSTRACT

El presente trabajo tiene como objetivo evaluar la utilidad de los estudios centellográficos in vitro e in vivo en el desarrollo de una formulación farmacéutica. Se eligio como trazador del proceso el radiofármaco 99mtc-ácido dietilentriaminopentaacético, que se incorporó a 4 formulaciones (f1 a f4) de comprimidos de ranitidina. Se llevaron a cabo estudios de estabilidad del radiofármaco en polvos, granulados y comprimidos. Las formulaciones en las cuales se verificó su estabilidad durante 24 horas (f2 y f4) fueronutilizadas para ensayos in vitro de disolución y desintegración y estudios en 6 voluntarios sanos. La desintegración in vitro e in vivo fué monitoreada por centellografía gamma. El radiofármaco presentó diferentes cinéticas de disolución a partir de f2 y f4, siendo las respectivas constantes que para la ranitidina en cada formulación en estudio. La centellografía permitió establecer una correlación entre las constantes de desintegración in vitro e in vivo. Esto permitiría predecir el comportamiento en el tracto gastro-intestinal de cada formulación a partir de la desintegración in vitro(AU)


Subject(s)
Comparative Study , Ranitidine/analysis , Radionuclide Imaging/instrumentation
12.
Acta farm. bonaer ; 19(3): 217-24, jul.-sept. 2000. ilus, tab
Article in Spanish | LILACS | ID: lil-288964

ABSTRACT

El presente trabajo tiene como objetivo evaluar la utilidad de los estudios centellográficos in vitro e in vivo en el desarrollo de una formulación farmacéutica. Se eligio como trazador del proceso el radiofármaco 99mtc-ácido dietilentriaminopentaacético, que se incorporó a 4 formulaciones (f1 a f4) de comprimidos de ranitidina. Se llevaron a cabo estudios de estabilidad del radiofármaco en polvos, granulados y comprimidos. Las formulaciones en las cuales se verificó su estabilidad durante 24 horas (f2 y f4) fueronutilizadas para ensayos in vitro de disolución y desintegración y estudios en 6 voluntarios sanos. La desintegración in vitro e in vivo fué monitoreada por centellografía gamma. El radiofármaco presentó diferentes cinéticas de disolución a partir de f2 y f4, siendo las respectivas constantes que para la ranitidina en cada formulación en estudio. La centellografía permitió establecer una correlación entre las constantes de desintegración in vitro e in vivo. Esto permitiría predecir el comportamiento en el tracto gastro-intestinal de cada formulación a partir de la desintegración in vitro


Subject(s)
Radionuclide Imaging/instrumentation , Ranitidine/analysis
SELECTION OF CITATIONS
SEARCH DETAIL
...