RESUMEN

BACKGROUND: There is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers. METHODS: We have synthesized MUC1-[18F] SFB and MUC1-FA-[18F] SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reaction. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds. RESULTS: Radiochemical yields for MUC1-[18F] SFB and MUC1-FA-[18F] SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which makes these approaches amenable to automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F] SFB and MUC1-FA-[18F] SFB, respectively. Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F] SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process. CONCLUSION: Initial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F] SFB may be a useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.

RESUMEN

Myocardial perfusion imaging (MPI) is one of the most commonly performed investigations in nuclear medicine studies. Due to the physical properties of the positron emitter gallium-68 (68Ga) and its availability from 68Ge/68Ga generator, together with the well-known coordination chemistry, we have synthesized 68Ga-NOTA- and 68Ga-NODAGA-rhodamine conjugates using a straightforward and a one-step simple reaction. Radiochemical yields were greater than 95% (decay corrected), with total synthesis time of less than 30 min. Radiochemical purities were always greater than 98% as assessed by TLC and HPLC. These synthetic approaches hold considerable promise as simple method for 68Ga-rhodamine conjugates preparation, with high radiochemical yield and purity. Biodistribution studies in normal Fischer rats at 60 min post-injection, demonstrated significant (~3% ID/g) uptake and favorable biodistribution profile for 68Ga-NOTA-rhodamine over 68Ga-NODAGA-rhodamine conjugate. These results demonstrate that 68Ga-NOTA-rhodamine conjugate may be useful as probe for the PET evaluation of myocardial perfusion.

Asunto(s)

Acetatos/química , Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo/química , Imagen de Perfusión Miocárdica/métodos , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , Rodaminas/síntesis química , Acetatos/farmacocinética , Animales , Radioisótopos de Galio/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Humanos , Ratones , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas Endogámicas F344 , Rodaminas/química , Rodaminas/farmacocinética , Distribución Tisular

RESUMEN

In an attempt to develop a new and rapid method for labeling peptides with (18)F, we have synthesized MUC1-[(18)F]SFB and BBN-[(18)F]SFB peptide conjugates using a convenient and one-step simple reactions. Radiochemical yields for MUC1-[(18)F]SFB and BBN-[(18)F]SFB peptide conjugates were greater than 70% in less than 30 min synthesis time, thus amenable for automation for the radiofluorination of peptides. in vitro tests on T47D breast cancer cells showed that the significant amounts of the radioconjugates were associated with cell fractions and held sufficient affinities and specificities toward T47D cell line. These radioconjugates may be useful as molecular probes for detecting and staging of breast cancer and monitoring tumor response to treatment.

Asunto(s)

Bombesina/análogos & derivados , Radioisótopos de Flúor/química , Mucina-1/química , Radiofármacos/síntesis química , Benzoatos/química , Bombesina/química , Neoplasias de la Mama/diagnóstico por imagen , Línea Celular Tumoral , Femenino , Humanos , Marcaje Isotópico/métodos , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Succinimidas/química

RESUMEN

In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [(124)I]-SIB- and [(124)I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [(124)I]-SIB- and [(124)I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30-40min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for (124)I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [(124)I]-SIP-folate conjugate over [(124)I]-SIB-folate conjugate. Biodistribution studies of [(124)I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [(124)I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment.

Asunto(s)

Transportadores de Ácido Fólico/metabolismo , Ácido Fólico/química , Tomografía de Emisión de Positrones/métodos , Animales , Transporte Biológico , Estabilidad de Medicamentos , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Humanos , Radioisótopos de Yodo , Yodobencenos/química , Células KB , Ratones , Piridinas/química , Radioquímica

RESUMEN

There is a need to develop more potent radiofluorinated folic acid conjugates for a better visualization of folate receptors that overexpress on many human cancers. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) and its availability in almost every positron-emission tomography center, new radiofluorinated [(18)F]-FDG-folate and methotrexate conjugates ([(18)F]-5 and [(18)F]-8) were synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-5 and [(18)F]-8 conjugates were prepared in high radiochemical yields (>80%) with total synthesis time of almost 20 min, and radiochemical purities were found to be greater than 98% without high-performance liquid chromatography purification, which make these approaches amenable for automation. In vitro tests on KB cell line showed that a significant amount of the radioconjugates were associated with the cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and hepatobiliary systems for [(18)F]-5 and [(18)F]-8 conjugates, respectively. Biodistribution studies in nude mice-bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable kinetics profile for [(18)F]-5 over the other conjugate. The uptake in the tumors was blocked by the excess coinjection of cold folic acid, suggesting the receptor-mediated process. These results demonstrate that [(18)F]-5 may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to the treatment.

Asunto(s)

Fluorodesoxiglucosa F18 , Transportadores de Ácido Fólico/metabolismo , Ácido Fólico/síntesis química , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Transporte Biológico , Técnicas de Química Sintética , Estabilidad de Medicamentos , Femenino , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Humanos , Marcaje Isotópico , Células KB , Metotrexato/química , Ratones , Neoplasias de la Boca/patología

RESUMEN

In an attempt to visualize folate receptors that overexpress on many cancers, [(18)F]-fluorobenzene and pyridinecarbohydrazide-folate/methotrexate conjugates ([(18)F]-1, [(18)F]-2-folates and [(18)F]-8, [(18)F]-9-MTXs) were synthesized by the nucleophilic displacement reactions using ethyl-trimethylammonium-benzoate and pyridinecarboxylate precursors. The intermediates ethyl [(18)F]-fluorinated benzene and pyridine esters were reacted with hydrazine to produce the [(18)F]-fluorobenzene and pyridinecarbohydrazides, followed by coupling with N-hydroxysuccinimide-folate/MTX. Radiochemical yields were greater than 80% (decay corrected), with total synthesis time of less than 45 min. Radiochemical purities were always greater than 97% without high-performance liquid chromatography purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiofluorination of folate derivatives with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that significant amount of the radioconjugates were associated with cell fractions, and in vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and partially by the hepatobiliary systems. Biodistribution studies in nude mice bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable biodistribution profile for [(18)F]-2-folate over the other conjugates. The uptake in the tumors was blocked by excess coinjection of folic acid, suggesting a receptor-mediated process. Micro-positron emission tomography images of nude mice bearing human KB cell line xenografts confirmed these observations. These results demonstrate that [(18)F]-2-folate may be useful as molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment.

Asunto(s)

Radioisótopos de Flúor , Transportadores de Ácido Fólico/metabolismo , Ácido Fólico/síntesis química , Neoplasias de la Boca/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radioquímica/métodos , Animales , Transporte Biológico , Transformación Celular Neoplásica , Estabilidad de Medicamentos , Femenino , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Humanos , Hidrazinas/química , Células KB , Metotrexato/síntesis química , Metotrexato/metabolismo , Metotrexato/farmacocinética , Ratones , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Piridinas/química , Factores de Tiempo

RESUMEN

SETTING: Randomised controlled trial of latent tuberculosis infection (LTBI) treatment in 10 clinics in Canada, Saudi Arabia and Brazil. OBJECTIVE: To identify early predictors of LTBI treatment adherence, including pre-treatment characteristics. DESIGN: Patients randomised to 4 months of rifampicin (RMP; n = 420) or 9 months of isoniazid (n = 427) were monitored for adherence using an electronic device. Outcomes were 1) treatment completion, defined as intake of >or=80% of the prescribed doses, and further categorised as completed within the allotted time or not; and 2) treatment regularity, measured by the time interval between doses. Relative risk (RR) and adjusted odds ratios (aOR) of patients' pre-treatment characteristics and adherence at first follow-up visit were calculated. RESULTS: Completion of treatment was higher with RMP (aOR 4.3, 95%CI 2.7-6.8). Early predictors (first follow-up visit) of non-adherence were late first visit attendance (RR for completion in time 0.9, 95%CI 0.8-0.98), >20% of missed doses (RR 0.4, 95%CI 0.3-0.6) and greater variation of hours between doses (0.209 vs. 0.131, P < 0.001). Serious adverse events were not associated with irregularity of treatment. CONCLUSION: The shorter RMP regimen was associated with better adherence. Patients with poor adherence could be identified at the first follow-up visit from their punctuality in follow-up, missed doses and variability of pill-taking.

Asunto(s)

Antituberculosos/uso terapéutico , Tuberculosis Latente/tratamiento farmacológico , Cumplimiento de la Medicación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Brasil/epidemiología , Canadá/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Isoniazida/uso terapéutico , Tuberculosis Latente/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rifampin/administración & dosificación , Rifampin/efectos adversos , Rifampin/uso terapéutico , Riesgo , Arabia Saudita/epidemiología , Factores de Tiempo , Adulto Joven

RESUMEN

OBJECTIVES: The aim of this study was to estimate the prevalence of depressive disorders and the influence of sociodemographic characteristics on primary healthcare (PHC) setting in Kuwait. SUBJECTS AND METHODS: A cross-sectional survey was conducted in PHC setting in Kuwait using the Beck Depression Inventory second edition questionnaire (BDI II) as a screening instrument, together with a sociodemographic questionnaire. A representative sample drawn from the target population consisted of 2,320 subjects of Kuwaiti nationality randomly selected from 18 PHC centers covering all Kuwait governorates during the period from April 2003 to January 2004. The target age group was 21-64 years. Participants were asked to complete the BDI II questionnaire consisting of 21 items reflecting the depressive disorder independently. Sociodemographic data such as sex, age, marital status, children, occupation, educational status, chronic diseases and social problems were included in the questionnaire. The optimum cutoff score for BDI II was estimated. RESULTS: A total of 2,320 participants completed the questionnaire, 1,082 (46.8%) male and 1,237 (53.2%) female; 860 (37.1%) screened positive for depressive symptoms, among whom 352 (15.3%) were male and 508 (21.7%) female. Of all participants, 163 (7.0%) were severely depressed, 314 (13.5%) moderately depressed and 383 (16.5%) mildly depressed. Depressive disorder was more prevalent among women than men, young than old, more among highly educated individuals, working participants, married individuals, and parents with 3 or more children. CONCLUSION: Depressive disorder is a highly prevalent condition among Kuwaiti patients attending PHC setting. Chronic diseases and social problems are risk factors for depressive disorder.

Asunto(s)

Depresión/epidemiología , Atención Primaria de Salud/estadística & datos numéricos , Adulto , Distribución por Edad , Estudios Transversales , Depresión/clasificación , Trastorno Depresivo/epidemiología , Femenino , Humanos , Kuwait/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Distribución por Sexo , Factores Socioeconómicos

RESUMEN

A non-invasive imaging technique capable of relating a signal from the beta-cells to their mass will be of immense value in understanding the progression of diabetes. Several molecular markers have indeed been identified and investigations are ongoing aimed at accomplishing the said goal. These include pancreatic islet antigen (IC-2), somatostatin receptors (SSTRs), and sulfonylurea receptors (SURs) on the pancreatic beta-cells. Therefore investigations exploiting the potential application of the radiolabeled ligands for these receptors for beta-cell imaging are receiving intensive research attention. Radioiodinated peptidomimetic based on beta-naphthylalanine and n-hexanediamine has been synthesized. The molecule was subjected to in vitro and in vivo evaluation. Radioligand binding studies on CHO cell line expressing the SSTR2 showed very low affinity. Nonetheless, biodistribution in normal mice showed significant uptake in the pancreas. There was partial blockage of the pancreatic uptake when excess of the peptidomimetic was coinjected. The result implies that the pancreatic uptake was receptor mediated but may not involve the SSTR2 and therefore warrants further investigation.

Asunto(s)

Células Secretoras de Insulina/diagnóstico por imagen , Radioisótopos de Yodo/química , Radiofármacos/síntesis química , beta-Alanina/análogos & derivados , Animales , Células CHO , Cricetinae , Células Secretoras de Insulina/metabolismo , Marcaje Isotópico/métodos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Endogámicos CBA , Cintigrafía , Distribución Tisular , beta-Alanina/química , beta-Alanina/metabolismo

RESUMEN

Melatonin demands that this hormone and its receptors be well understood. With this aim in mind, synthetic melatonin was radioiodinated with no-carrier-added (n.c.a.) sodium iodide-123 using in situ generated peracetic acid as oxidizing agent for electrophilic iodination at room temperature. The radiochemical yield was typically greater than 80% after 20 min reaction time especially when relatively small amounts of activities were used (

Asunto(s)

Melatonina/análogos & derivados , Melatonina/síntesis química , Animales , Cromatografía Líquida de Alta Presión , Femenino , Radioisótopos de Yodo , Marcaje Isotópico , Melatonina/farmacocinética , Ratones , Ratones Endogámicos CBA , Distribución Tisular

RESUMEN

Numerous molecular entities with diverse structures have been radiolabeled and investigated as potential infection and inflammation detection agents. However, none of these molecules have gained the acceptance of gallium citrate or radiolabeled autologous white blood cells. We have radioiodinated interleukin-8 using two different methods and tested the biological behavior of the products in mice. As expected, the direct radioiodinated material displayed extensive in vivo deiodination. The use of pyridine-based prosthetic label yielded a product with better kinetics than the direct radioiodination method and showed a better target to non-target ratio. Nonetheless, this method is not suited for labeling of bioactive peptides such as the title peptide because of the very high specific activity required to prevent cytotoxic effects in a human application.

Asunto(s)

Infecciones por Escherichia coli/diagnóstico por imagen , Infecciones por Escherichia coli/metabolismo , Interleucina-8/farmacocinética , Neutrófilos/diagnóstico por imagen , Neutrófilos/metabolismo , Animales , Células Cultivadas , Interleucina-8/química , Radioisótopos de Yodo/química , Radioisótopos de Yodo/farmacocinética , Marcaje Isotópico/métodos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos CBA , Especificidad de Órganos , Cintigrafía , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Distribución Tisular

RESUMEN

We have synthesized 2-[(18)F]-fluoroisonicotinic acid hydrazide by nucleophilic displacement reaction on ethyl-2- (trimethylammonium)-isonicotinate precursor in acetonitrile. Kryptofix 222 was used as the phase transfer catalyst. The intermediate fluorinated ethyl ester reacted with hydrazine hydrate to produce the hydrazide. Excellent radiochemical yield was attained with total synthesis time of approximately 60 min. Biological evaluation was performed in bacterial cells and biodistribution in normal as well as E. coli infected CBA/J mice. It was found that the S. pneumoniae cells retained the radiotracer in an in vitro assay. The tracer showed positive localization at the infection/inflammation site in E. coli infected mice.

Asunto(s)

Infecciones por Escherichia coli/diagnóstico por imagen , Radioisótopos de Flúor , Infecciones/diagnóstico por imagen , Tuberculosis Pulmonar/diagnóstico por imagen , Animales , Modelos Animales de Enfermedad , Humanos , Hidrazinas/síntesis química , Ácidos Isonicotínicos/síntesis química , Ratones , Ratones Endogámicos BALB C , Cintigrafía

RESUMEN

2-[18F]-Fluoroisonicotinic acid hydrazide was synthesized by nucleophilic displacement reaction on ethyl-2- (trimethylammonium)-isonicotinate precursor in acetonitrile. Kryptofix 222 was used as the phase transfer catalyst. The intermediate fluorinated ethyl ester reacted with hydrazine hydrate to produce the hydrazide in excellent radiochemical yield. The overall radiochemical yield was greater than 70% with total synthesis time of approximately 60 minutes. Biological evaluation was performed in bacterial cells and biodistribution in normal CBA/J mice. It was found that the S. pneumoniae cells retained the radiotracer in an in vitro assay.

Asunto(s)

Hidrazinas/síntesis química , Hidrazinas/farmacocinética , Ácidos Isonicotínicos/síntesis química , Ácidos Isonicotínicos/farmacocinética , Streptococcus pneumoniae/metabolismo , Animales , Células Cultivadas , Estudios de Factibilidad , Femenino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos CBA , Especificidad de Órganos , Radiometría/métodos , Cintigrafía , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Valores de Referencia , Distribución Tisular , Tuberculosis/diagnóstico por imagen , Tuberculosis/metabolismo

RESUMEN

Radiolabeled peptides continue to emerge as potential radiopharmaceuticals for targeting several diseases such as cancer, infection and inflammation and even tissue and organ rejection. The classical method for labeling these molecules has been the electrophilic route. Evidence suggests that most molecules labeled via this route perturb their biological activity. Moreover, this method is not applicable to peptides lacking a tyrosine moiety in their structure. Hence, there is the need to develop alternate methods such as the prosthetic approach. We have optimized a solid-state radioiodination by exchange to produce [123I]-metaiodobenzylguanidine ([123I]-mIBG). The mIBG served as a precursor to obtain an activated N-succinimidyl ester for efficient coupling to amine functions in peptides, preferably the lysine group(s). The method was used to label a model chemotactic peptide and evaluated in vivo.

Asunto(s)

Radioisótopos de Yodo , Yodobenzoatos/síntesis química , Péptidos , Radiofármacos/síntesis química , Animales , Estabilidad de Medicamentos , Radioisótopos de Yodo/farmacocinética , Yodobenzoatos/química , Yodobenzoatos/farmacocinética , Ratones , Péptidos/química , Péptidos/farmacocinética , Radiofármacos/química , Radiofármacos/farmacocinética , Distribución Tisular