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/metabolismoRESUMEN
Prosthetic radioiodination methods were developed to facilitate the labeling of proteins devoid of tyrosine(s) or when these moieties are crucial for biological activity. This method involves the use of the so-called Bolton-Hunter-type reagents. However, the in vivo instability of the label prompted the search for more stable groups. Although these second generation reagents have worked well with proteins and peptides, the current reaction scheme takes a long time to perform. A simplified method may be more appropriate especially from radiation safety point of view. More importantly, for short-lived halogens, advantage may be gained utilizing a shorter reaction time. Recently we reported on the radioiodination of interleukin-8 (IL-8) using the pyridine carboxylate-derived activated ester. We have successfully conjugated this prosthetic group to tri- and tetrapeptides harboring the somatostatin (SST) receptor recognition units and characterized by HPLC and MS. The radioiodination was accomplished using the Iodogen method in a reasonable yield (mean=60%). The total synthesis time was approximately 60 min, which was 3-4 times shorter than the classical two-step method. Preliminary biodistribution of the radiolabeled peptide showed uptake in some of the organs known to express SST receptors. Injection of a low specific activity tracer significantly decreased the retention of radioactivity in these organs.
Asunto(s)
Oligopéptidos/química , Radiofármacos/química , Animales , Cromatografía Líquida de Alta Presión , Radioisótopos de Yodo/química , Radioisótopos de Yodo/farmacocinética , Marcaje Isotópico , Ratones , Ratones Endogámicos CBA , Oligopéptidos/farmacocinética , Radiofármacos/farmacocinética , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Distribución Tisular , Compuestos de Trimetilestaño/química , Tirosina/químicaRESUMEN
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 TisularRESUMEN
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 , CintigrafíaRESUMEN
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/metabolismoRESUMEN
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 TisularRESUMEN
The success of (111)In-pentetreotide as a cancer-imaging agent has given impetus to the search for other peptide-based radiopharmaceuticals. The labeling with Tc-99m has become even more attractive because of the ready availability and near ideal physical properties. Additionally, the kinetics of the peptide-receptor interactions favors the radiolabeling with technetium-99m. A somatostatin analog RC-160 has been labeled with Tc-99m using the "3+1" mixed ligand approach utilizing the NNS/S coordination sites. The ternary complex was formed in greater than 95% within 30 min by simultaneous reduction and complexation of technetium-99m pertechnetate. The Tc-99m and the surrogate rhenium complexes showed similar chromatographic behavior. The complex was evaluated by in vitro receptor binding studies carried out on HTB-121 breast cancer cell line and biodistribution studies performed in normal mice. Our findings suggest that RC-160 can be labeled by the mixed ligand approach with the complex retaining its biological activity and warrants further studies.
Asunto(s)
Radiofármacos/síntesis química , Somatostatina/síntesis química , Animales , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Ligandos , Ratones , Ensayo de Unión Radioligante , Somatostatina/análogos & derivados , Somatostatina/farmacocinética , Compuestos de Tecnecio/química , Distribución Tisular , Células Tumorales Cultivadas/metabolismoRESUMEN
The increasing demand for radiolabeled metaiodobenzylguanidine (mIBG) prompted the need to obtain the radiopharmaceutical by a reliable, routine and simple synthetic method for batch production. The production of mIBG labeled with either 123I or 124I has been optimized by modifying literature methods that involve solid-state exchange reaction on "cold" mIBG facilitated by ammonium sulfate. The radiochemical yield and purity of radioiodinated mIBG generally exceeded 80 and 98%, respectively, with specific activity of > 50 mCi/mg.
Asunto(s)
3-Yodobencilguanidina/síntesis química , Radioisótopos de Yodo , Radiofármacos/síntesis química , Sulfato de Amonio , Indicadores y ReactivosRESUMEN
PURPOSE: Whole-body fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) scanning has been useful in the management of breast cancer. However, F-18 FDG uptake sometimes has been associated with benign breast disease. Four cases are reported of F-18 FDG breast uptake caused by infectious or inflammatory mastitis that mimics malignant disease. METHODS AND RESULTS: Two women had F-18 FDG whole-body scans for the evaluation of a large breast mass after inconclusive results of ultrasonography. In both cases, intense focal F-18 FDG breast uptake was noted that mimicked breast cancer. Histologic examination showed, in one patient, chronic granulomatous infiltration that likely represented tuberculous mastitis, because she showed a good clinical response to empirical anti-tuberculous treatment. The second patient had lactational changes associated with acute inflammation, and the culture grew Staphylococcus aureus. The breast mass completely disappeared 3 weeks after a course of antibiotic treatment. The other two patients had staging F-18 FDG PET scans 1 and 12 months after lumpectomy for breast carcinoma to detect residual, recurrent, or metastatic disease. Both scans showed a ring-like uptake in the involved breast, with superimposed intense focal uptake suggesting tumor necrosis centrally and malignant foci peripherally. In both cases, histologic examination revealed hemorrhagic inflammation secondary to postsurgical hematomas and no evidence of malignancy. CONCLUSION: Acute or chronic infectious mastitis and postsurgical hemorrhagic inflammatory mastitis should be considered in patients who have a breast mass, especially those with a history of tenderness or surgery.
Asunto(s)
Enfermedades de la Mama/diagnóstico por imagen , Mama/diagnóstico por imagen , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Radiofármacos , Tomografía Computarizada de Emisión , Adulto , Neoplasias de la Mama/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Hematoma/diagnóstico por imagen , Humanos , Mastitis/diagnóstico por imagen , Mastitis/microbiología , Persona de Mediana Edad , Hemorragia Posoperatoria/diagnóstico por imagen , Infecciones Estafilocócicas/diagnóstico por imagen , Tuberculosis/diagnóstico por imagenRESUMEN
The deficiency of adhesion molecules on leukocytes could severely impair their ability to migrate and perform effective immunological functions leading to clinical situation such as LAD (leukocyte adhesion deficiency) syndrome. We investigated the effects of blocking anti-LFA-1 alpha and ICAM-1 antibody-treated 99mTc-labeled leukocytes on the migration and localization to the site of E. coli-induced acute infection in CBA/J mice. A significant inhibition of migration and localization of antibody-treated leukocytes to the site of infection was observed, reaffirming the vital role of these adhesion molecules, especially during scintigraphic examination of patients for deep infections or abscess using labeled leukocytes.
Asunto(s)
Infecciones por Escherichia coli/diagnóstico , Molécula 1 de Adhesión Intercelular/fisiología , Leucocitos/fisiología , Antígeno-1 Asociado a Función de Linfocito/fisiología , Tecnecio , Enfermedad Aguda , Animales , Anticuerpos/inmunología , Movimiento Celular , Femenino , Ratones , Ratones Endogámicos CBARESUMEN
Technetium-99m complexes of somatostatin and analogs were synthesized following the introduction of sulfhydryl groups with 2-iminothiolane (Traut's Reagent). In rats the complex was taken up by the liver, kidneys, adrenals, lungs and the pancreas. Analysis of urine samples of treated rats showed that the radiochemicals have reasonably good in vivo stability. This implies that the complexes may be potentially useful for biochemical characterization of somatostatin receptors and also in scintigraphic detection of somatostatin receptor positive tumors, especially for metastatic deposits in patients on somatostatin therapy.
Asunto(s)
Compuestos de Organotecnecio/síntesis química , Somatostatina/análogos & derivados , Animales , Quelantes/química , Reactivos de Enlaces Cruzados/química , Estabilidad de Medicamentos , Imidoésteres/química , Marcaje Isotópico/métodos , Cinética , Masculino , Compuestos de Organotecnecio/metabolismo , Compuestos de Organotecnecio/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Somatostatina/síntesis química , Somatostatina/farmacocinética , Distribución TisularRESUMEN
In vivo radiolabeled liposome uptake in 5 sham-operated, 7 coarctation-induced hypertensive, and 8 atherosclerotic arterial walls from New Zealand White rabbits was compared to determine the mechanism of arterial wall uptake of liposomes. Uptake between the three groups was significantly different (P less than 0.001) with a 3-fold difference in uptake between the sham-operated and hypertensive groups and the hypertensive and atherosclerotic groups. Liposome uptake was significantly higher in the atherosclerotic group of animals (P less than 0.05). Avidin-biotin immunoperoxidase staining for monocyte/macrophage cells revealed that liposome uptake increased concomitantly with arterial wall monocyte/macrophage cellular invasion and that liposome localization, determined by autoradiography, paralleled the monocyte/macrophage cellular distribution in both hypertensive and atherosclerotic arterial walls. This study provides the first direct evidence that liposomes can escape from the circulation and enter the diseased arterial wall. Furthermore, it suggests that one possible mechanism of arterial wall uptake of liposomes is via the monocyte/macrophage cell which avidly and preferentially engulfs liposomes and then passively carries them into the arterial wall during hypertensive and atherosclerotic lesion development. Liposomes could potentially be used to carry agents into the arterial wall in the study of arterial wall lesion development.
Asunto(s)
Aorta/metabolismo , Arteriosclerosis/metabolismo , Hipertensión/metabolismo , Liposomas/farmacocinética , Macrófagos/fisiología , Monocitos/fisiología , Animales , Aorta/patología , Arteriosclerosis/sangre , Arteriosclerosis/patología , Autorradiografía , Presión Sanguínea , Colesterol/sangre , Hipertensión/patología , Hipertensión/fisiopatología , Inmunohistoquímica , Macrófagos/patología , Masculino , Monocitos/patología , ConejosRESUMEN
The hexachlorotechnetate reagent has been used to synthesize lipophilic complexes of technetium-99m with polydentate ligands, using ligand exchange reactions and acetonitrile as an aprotic solvent. The complexes isolated were partially characterized by chromatographic (paper and HPLC) and electrophoretic methods. Preliminary data on biodistribution studies, carried out in rabbits, are also presented. This work documents that the hexachlorotechnetate reagent is a suitable intermediate for the rapid synthesis of new lipophilic complexes of technetium-99m.
Asunto(s)
Compuestos de Organotecnecio/síntesis química , Animales , Cromatografía Líquida de Alta Presión , Hígado/metabolismo , Compuestos de Organotecnecio/farmacocinética , ConejosRESUMEN
The radiochemical syntheses of methyl 2-[123I]-iodoisonicotinate, 2-[123I]-iodoisonicotinic acid hydrazide and 2-[124I]-iodoisonicotinic acid hydrazide was accomplished. Iodine-123 was incorporated in the methyl ester molecule by an exchange reaction in glacial acetic acid. The average efficiency of iodine exchange reaction was (92.6 +/- 4.5)%. This radiotracer was extracted with ether and the solvent was evaporated. The residue was re-dissolved in anhydrous ethanol and treated with hydrazine under anhydrous conditions to obtain 2-[123I]-iodoisonicotinic acid hydrazide. The overall radiochemical yield was 69%. Biodistribution data of both radio-tracers in male Sprague-Dawley rats were collected. This is the first report of SPECT radiopharmaceuticals which may be useful for differential diagnosis of intracranial masses (tuberculoma vs glioma), and CNS tuberculosis in immunosuppressed subjects.
Asunto(s)
Isoniazida/análogos & derivados , Ácidos Isonicotínicos/síntesis química , Tuberculoma/diagnóstico por imagen , Animales , Disponibilidad Biológica , Encefalopatías/diagnóstico por imagen , Radioisótopos de Yodo , Isoniazida/síntesis química , Isoniazida/farmacocinética , Ácidos Isonicotínicos/farmacocinética , Marcaje Isotópico/métodos , Masculino , Radioquímica , Cintigrafía , Ratas , Ratas EndogámicasRESUMEN
Using five sham-operated and seven aortic coarctation-induced hypertensive New Zealand White rabbits intravenously injected with neutral small unilamellar vesicles loaded with [111In]nitrilotriacetic acid, we demonstrated in vivo that the normal aortic arterial wall participates in liposome uptake and that this uptake is increased in the hypertensive aortic wall by approximately threefold (p less than or equal to 0.0001). Among the three regions examined, aortic arch, thoracic aorta, and lower abdominal aorta, the difference in uptake between the normotensive and hypertensive arterial walls was significantly different, p less than or equal to 0.05, p less than or equal to 0.0001, and p less than 0.05, respectively. The uptake by the different regions of the hypertensive arterial wall is consistent with the pathological changes present in these areas. Furthermore, the extent of liposome uptake by the aortic wall is strongly correlated with the height of the blood pressure (r = 0.85, p = 0.001, n = 11). We conclude that neutral small unilamellar liposomes can be used to carry agents into the arterial wall in vivo in the study of hypertensive vascular disease and could be especially useful for the delivery of pharmacologically or biologically active agents that would otherwise be inactivated within the circulation or are impermeable to the arterial wall.
Asunto(s)
Aorta/metabolismo , Hipertensión/metabolismo , Liposomas/metabolismo , Animales , Aorta/patología , Presión Sanguínea , Portadores de Fármacos , Hipertensión/patología , Radioisótopos de Indio , Masculino , ConejosRESUMEN
The radiopharmaceutical 6 beta-[124I]iodomethyl-19-nor-cholest-5(10)-en-3 beta-ol (NCL-6-124I) was synthesized. The product was less sensitive to autoradiolytic decomposition in chloroform, than when stored as an injectable solution at 5 degrees C.