RESUMEN
Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Nortropanos/síntesis química , Nortropanos/metabolismo , Simportadores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Fluoxetina/análogos & derivados , Fluoxetina/metabolismo , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Estructura Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Nortropanos/farmacología , Paroxetina/metabolismo , Piperazinas/metabolismo , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismoRESUMEN
We have shown that 1H NMR can serve as a suitable analytical tool for the assessment of relative amounts of d,l and meso HM-PAO isomers in a diastereomeric mixture and for the determination of the purity of either one of the two diastereomers alone. Therefore, we believe that this method will be useful for quality control in both academic and government regulatory laboratories as well as for radiopharmaceutical manufacturers. In addition, this analytical tool can provide rapid screening of possible suitable stereospecific reducing agents for the preferential formation of the d,l HM-PAO diastereomer without the necessity of completely working up the reduction reaction mixture.
Asunto(s)
Espectroscopía de Resonancia Magnética , Compuestos Organometálicos/análisis , Oximas/análisis , Cristalografía , Isomerismo , Estereoisomerismo , Tecnecio , Exametazima de Tecnecio Tc 99m , Difracción de Rayos XRESUMEN
Labeling of human sarcoma-associated murine monoclonal antibody (MAb) 23H7 with 67Ga and 111In by the bifunctional ligand method is reported. 67Ga was chelated to the MAb via desferrioxamine B and 111In via the cyclic anhydride of DTPA. Higher specific activity was obtained with 67Ga (4-5 microCi/micrograms) as compared with 111In (2 microCi/micrograms). The binding capacity of the MAb was confirmed by repeated indirect immuno-fluorescence assays performed before and after labeling. A fast blood clearance was observed: 33% recovered dose (R.D.) blood level 3 h post-injection as compared with 56% after injection of control polyclonal IgG. Preliminary results on chemically induced sarcoma bearing mice showed a relatively high tumor uptake of the labeled antibody.
Asunto(s)
Anticuerpos Monoclonales , Radioisótopos de Galio , Indio , Radioisótopos de Yodo , Marcaje Isotópico/métodos , Radioisótopos , Sarcoma/inmunología , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antineoplásicos , Humanos , Ratones , Sarcoma Experimental/metabolismo , Distribución TisularRESUMEN
A preliminary study was conducted to compare the BrK alpha/RbK alpha peak intensity ratio in colorectal cancer (CRC) patients and healthy subjects (controls) in Israel. Blood samples were obtained from 61 CRC patients and 124 controls. The controls represent a normal population from different areas in Israel. Three hundred microliters of wet whole blood samples were analyzed by the EDXRF method. A weighted mean of 2.45 +/- 0.38 Br/Rb ratio was obtained for CRC patients, as compared with 3.28 +/- 0.40 Br/Rb ratio for controls. The mean value for controls represents only 112 subjects, since 12 individuals of the control group suffered from some other diseases and therefore were not included for the mean value calculation in this group. The results indicate that the Br/Rb ratio in CRC patients is significantly lower (p < 0.05) than in controls. No significant difference was found in Br/Rb ratio correlated to age and sex. It was not possible to draw final conclusion concerning the relationship between the Br/Rb ratio and the malignancy stage, since there was a relatively small number of cases in each stage under investigation.
Asunto(s)
Bromo/sangre , Neoplasias Colorrectales/sangre , Rubidio/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Recolección de Muestras de Sangre , Neoplasias Colorrectales/diagnóstico , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Factores Sexuales , Análisis Espectral , Rayos XRESUMEN
The effect of cis-DDP treatment with and without selenite and selenocistamine was studied on kidneys of tumor-bearing mice. The amounts of cis-DDP, selenite, and selenocistamine injected were chosen so as to be compatible with the treatment of humans. The animals were sacrificed at 7, 14, and 28 d after treatment. The kidneys were removed and subjected to trace element analysis by a novel X-ray fluorescence (XRF) method and for pathological assessment. The results show that following treatment with cis-DDP, K, Fe, Cu, and Zn reach a maximum level after 7 d; K, Fe, and Cu levels were significantly reduced by the addition of selenite. The level of Zn was reduced only in groups treated with selenite whereas that of K and Cu was reduced also in groups treated with selenocistamine with and without cis-DDP. The greatest increase in Pt and Se levels was reached 1 wk after injection with cis-DDP, with and without selenocompounds, and in the case of Pt was partly reduced by addition of selenite. Se returned to control values 2 wk after injection, although Pt was still high in all groups 2 and 4 wk after injection. The results corroborate the findings of our previous studies. The effect of selenocistamine in cis-DDP treated mice was partly insufficient. The pathological examination of the kidneys did not show any differences in the effect of various additives during the study.
Asunto(s)
Cisplatino/farmacología , Cistamina/análogos & derivados , Riñón/efectos de los fármacos , Neoplasias Experimentales/metabolismo , Compuestos de Organoselenio/farmacología , Selenito de Sodio/farmacología , Oligoelementos/metabolismo , Animales , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Cobre/metabolismo , Cistamina/administración & dosificación , Cistamina/farmacología , Cistamina/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Hierro/metabolismo , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/uso terapéutico , Potasio/metabolismo , Selenito de Sodio/administración & dosificación , Selenito de Sodio/uso terapéutico , Espectrometría por Rayos XRESUMEN
The protective effect of polyvinylpyrrolidone of mol. wt 10,000 and 40,000, on sheep erythrocytes irradiated up to 13 kGy, and stored for one month at 4 degrees C was studied. Addition of these compounds at a level of 10-15% reduced hemolysis from 90% in irradiated erythrocyte solution to approximately 10%. The high efficiency of this protective agent is discussed.
Asunto(s)
Eritrocitos/efectos de la radiación , Povidona/farmacología , Protectores contra Radiación , Animales , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , OvinosRESUMEN
The Br/Rb ratio in kidneys of normal and tumor-bearing mice was studied and a significant difference was found between the two groups. The mice were treated with cis-DDP with and without selenite, with selenite alone, and compared with controls. The animals were sacrificed 7d, 14d, and 21-28d after treatment. The kidneys were removed and subjected to Br and Rb determination by a novel X-ray fluorescence (XRF) method. The results are presented in terms of estimated net count rates under the BrK alpha and RbK alpha peaks. No significant differences were found in Br and Rb levels or in the Br/Rb ratio in kidneys of treated and untreated mice belonging to the same group-normals or lung carcinoma inoculated. However, there was a significant difference in the Br/Rb ratio between the two tested groups (normals and inoculated). Preliminary results on the Br/Rb ratio obtained from normal and malignant tissues of colorectal cancer (CRC) patients and from mice inoculated with melanoma, show the same trend as those from the group of mice with lung carcinoma. In all three groups tested the Br/Rb ratio was 2-4 times higher in normal than in malignant tissue.
Asunto(s)
Bromo/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Cisplatino/uso terapéutico , Riñón/efectos de los fármacos , Rubidio/metabolismo , Animales , Estudios de Evaluación como Asunto , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Valores de Referencia , Espectrometría por Rayos X , EstereoisomerismoRESUMEN
Monoclonal antibody (MAb) 23H7 is a hybridoma-derived IgG that is generated following fusion of mouse myeloma cell line P3U1 and spleen cells from BALB/c mice hyperimmunized with a human fibrosarcoma. It detects a mesenchymal antigen of 23KD expressed on human sarcoma tissues and other neoplasms, including myeloid leukemias, but it rarely binds to normal tissues. The MAb 23H7 was labeled with 67Ga and 111In using the bifunctional ligand method. The 67Ga was chelated to the MAb via desferrioxamine B, while 111In was chelated via the cyclic anhydride of diethylenetriamine pentaacetic acid. Higher specific activity was obtained with 67Ga than with 111In (4.5 and 2 muCi/microgram, respectively); both gave stable complexes. When 23H7 was labeled with 125I, considerable breakdown was observed. This, together with the physical shortcomings of this isotope, emphasizes the advantages of labeling with 111In and 67Ga. The rapid blood clearance of the labeled sarcoma-associated MAb may be beneficial for early tumor uptake and for imaging shortly after injection.