RESUMEN
Vertebral fracture (VF) locations are bimodally distributed in the spine. The association between VF and bone attenuation (BA) measured on chest CT scans varied according to the location of VFs, indicating that other factors than only BA play a role in the bimodal distribution of VFs. INTRODUCTION: Vertebral fractures (VFs) are associated with low bone mineral density but are not equally distributed throughout the spine and occur most commonly at T7-T8 and T11-T12 ("cVFs") and less commonly at T4-T6 and T9-T10 ("lcVF"). We aimed to determine whether associations between bone attenuation (BA) and VFs vary between subjects with cVFs only, with lcVFs only and with both cVFs and lcVFs. METHODS: Chest CT images of T4-T12 in 1237 smokers with and without COPD were analysed for prevalent VFs according to the method described by Genant (11,133 vertebrae). BA (expressed in Hounsfield units) was measured in all non-fractured vertebrae (available for 10,489 vertebrae). Linear regression was used to compare mean BA, and logistic regression was used to estimate the association of BA with prevalent VFs (adjusted for age and sex). RESULTS: On vertebral level, the proportion of cVFs was significantly higher than of lcVF (5.6% vs 2.0%). Compared to subjects without VFs, BA was 15% lower in subjects with cVFs (p < 0.0001), 25% lower in subjects with lcVFs (p < 0.0001) and lowest in subjects with cVFs and lcVFs (- 32%, p < 0.0001). The highest ORs for presence of VFs per - 1SD BA per vertebra were found in subjects with both cVFs and lcVFs (3.8 to 4.6). CONCLUSIONS: The association between VFs and BA differed according to VF location. ORs increased from subjects with cVFs to subjects with lcVFs and were highest in subjects with cVFs and lcVFs, indicating that other factors than only BA play a role in the bimodal VF distribution. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00292552.
Asunto(s)
Enfermedades Óseas Metabólicas , Fracturas de la Columna Vertebral , Densidad Ósea , Humanos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Columna Vertebral , Tomografía Computarizada por Rayos XRESUMEN
In smokers and former smokers from the ECLIPSE cohort, there is an association between prevalent vertebral fractures (VFs) and coronary artery calcification (CAC). Chest CT scans provide the opportunity to evaluate VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions. INTRODUCTION: Prevalence of VFs among smokers and patients with chronic obstructive pulmonary disease (COPD) is high, and an association between CAC and osteoporosis has been described. We investigated the associations between VFs and CAC (expressed in Agatston score) in (former) smokers. METHODS: Current and former smokers from the ECLIPSE study (designed to determine underlying COPD progression mechanisms) were studied. Baseline Agatston score (zero (0), medium (1-400), or high (> 400)), baseline bone attenuation (BA), and prevalent and incident VFs (vertebrae T1-L1) were assessed on CT. RESULTS: A total of 586 subjects were included (mean age 59.8 ± 8.3; 62.3% men; 70.1% with COPD; 21.0% with prevalent VFs; 196 with zero, 266 with medium, and 124 with high Agatston score). Of these, 23.4% suffered incident VFs within 3 years. In multivariate models, prevalent VFs were associated with medium (1.83 [95% CI 1.01-3.30]) and with high (OR = 3.06 [1.45-6.47]) Agatston score. After adjustment for BA, prevalent VFs were still associated with high (OR = 2.47 [1.13-5.40]), but not significantly with medium Agatston score (OR = 1.57 [0.85-2.88]). Similarly, after adjustment for BA, high (OR = 2.06 [1.02-4.13]) but not medium Agatston score (OR = 1.61 [0.88-2.94]) was associated with prevalent VFs. Agatston score at baseline was not associated with short-term VF incidence. CONCLUSION: In (former) smokers, there was an association between prevalent VFs and Agatston score. Chest CT scans provide the opportunity to also evaluate for VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions.
Asunto(s)
Enfermedad de la Arteria Coronaria , Osteoporosis , Fumadores , Fracturas de la Columna Vertebral , Calcificación Vascular , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/epidemiología , Osteoporosis/etiología , Factores de Riesgo , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiología , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/epidemiología , Calcificación Vascular/etiologíaRESUMEN
CT scans performed to evaluate chronic obstructive pulmonary disease (COPD) also enable evaluation of bone attenuation (BA; a measure of bone density) and vertebral fractures (VFs). In 1239 current/former smokers with (n = 999) and without (n = 240) COPD, the combination of BA and prevalent VFs was associated with the incident VF risk. INTRODUCTION: Chest CT scans are increasingly used to evaluate pulmonary diseases, including COPD. COPD patients have increased risk of osteoporosis and VFs. BA on CT scans is correlated with bone mineral density and prevalent VFs. The aim of this study was to evaluate the association between BA and prevalent VFs on chest CT scans, and the risk of incident VFs in current and former smokers with and without COPD. METHODS: In participants of the ECLIPSE study with baseline and 1-year and 3-year follow-up CT scans, we evaluated BA in vertebrae T4-T12 and prevalent and incident VFs. RESULTS: A total of 1239 subjects were included (mean age 61.3 ± 8.0, 61.1% men, 999 (80.6%) COPD patients). The mean BA was 155.6 ± 47.5 Hounsfield Units (HU); 253 (20.5%) had a prevalent VF and 296 (23.9%) sustained an incident VF within 3 years. BA and prevalent VFs were associated with incident VFs within 1 (per - 1SD HR = 1.38 [1.08-1.76] and HR = 3.97 [2.65-5.93] resp.) and 3 years (per - 1SD HR = 1.25 [1.08-1.45] and HR = 3.10 [2.41-3.99] resp.), while age, sex, body mass index (BMI), smoking status and history, or presence of COPD was not. In subjects without prevalent VFs and BA, and for 1-year incidence, BMI values were associated with incident fractures (1 year, BA per - 1SD HR = 1.52 [1.05-2.19], BMI per SD HR = 1.54 [1.13-2.11]; 3 years, per - 1SD HR = 1.37 [1.12-1.68]). CONCLUSIONS: On CT scans performed for pulmonary evaluation in (former) smokers with and without COPD, the combination of BA and prevalent VFs was strongly associated with the short-term risk of incident VFs.
Asunto(s)
Densidad Ósea/fisiología , Fracturas Osteoporóticas/etiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Fracturas de la Columna Vertebral/etiología , Adulto , Anciano , Ex-Fumadores , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Medición de Riesgo/métodos , Fumar/efectos adversos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/fisiopatología , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Capacidad Vital/fisiologíaRESUMEN
X-ray, CT and DXA enable diagnosis of vertebral deformities. For this study, level of agreement of vertebral deformity diagnosis was analysed. We showed that especially on subject level, these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients. INTRODUCTION: X-ray and CT are frequently used for pulmonary evaluation in patients with chronic obstructive pulmonary disease (COPD) and also enable to diagnose vertebral deformities together with dual-energy X-ray absorptiometry (DXA) imaging. The aim of this research was to study the level of agreement of these imaging modalities for diagnosis of vertebral deformities from T4 to L1. METHODS: Eighty-seven subjects (mean age of 65; 50 males; 57 COPD patients) who had X-ray, chest CT (CCT) and DXA were included. Evaluable vertebrae were scored twice using SpineAnalyzer™ software. ICCs and kappas were calculated to examine intra-observer variability. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUROC) were calculated to compare vertebral deformities diagnosed on the different imaging modalities. RESULTS: ICCs for height measurements were excellent (> 0.94). Kappas were good to excellent (0.64-0.77). At vertebral level, the AUROC was 0.85 for CCT vs. X-ray, 0.74 for DXA vs. X-ray and 0.77 for DXA vs. CCT. Sensitivity (51%-73%) and PPV (57%-70%) were fair to good; specificity and NPV were excellent (≥ 96%). At subject level, the AUROC values were comparable. CONCLUSIONS: Reproducibility of height measurements of vertebrae is excellent with all three imaging modalities. On subject level, diagnostic performance of CT (PPV 79-82%; NPV 90-93%), and to a slightly lesser extend of DXA (PPV 73-77%; NPV 80-89%), indicates that these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients.
Asunto(s)
Fracturas Osteoporóticas/diagnóstico por imagen , Curvaturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/diagnóstico por imagen , Vértebras Torácicas/diagnóstico por imagen , Absorciometría de Fotón/métodos , Anciano , Femenino , Humanos , Vértebras Lumbares/diagnóstico por imagen , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Variaciones Dependientes del Observador , Fracturas Osteoporóticas/complicaciones , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Radiografía , Radiografía Torácica , Reproducibilidad de los Resultados , Curvaturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/complicacionesRESUMEN
Nosocomial outbreaks of infection due to non-typeable Haemophilus influenzae (NTHi) are rarely described. There are a few published reports that suggest that elderly patients with underlying pulmonary disease are at risk and that person-to-person spread is key to disease transmission. During the summer months of 2005, we documented an outbreak of NTHi infections in a Veterans Affairs nursing home. Thirteen patients developed conjunctivitis or lower respiratory infection involving a beta-lactamase-negative biotype III NTHi isolate, with an indistinguishable SmaI macrorestriction pattern. Patients were elderly males usually with underlying cardiac and pulmonary disease. A case-control study failed to demonstrate any specific significant risk factor for NTHi infection and there was no evidence of spatial clustering of cases within the nursing home. A random throat culture survey involving nursing home patients during the outbreak showed that only one of 19 persons was colonized with NTHi. The outbreak concluded following appropriate treatment and an emphasis on universal and respiratory droplet precautions. All patients recovered and a specific inciting event for the outbreak was never defined. Literature review revealed a spectrum of responses to nosocomial NTHi infections and a lack of consensus regarding the infection control approach towards NTHi outbreaks.
Asunto(s)
Portador Sano/microbiología , Infección Hospitalaria/microbiología , Brotes de Enfermedades/prevención & control , Infecciones por Haemophilus/epidemiología , Haemophilus influenzae/patogenicidad , Anciano , Anciano de 80 o más Años , Técnicas de Tipificación Bacteriana , Infección Hospitalaria/epidemiología , Infección Hospitalaria/prevención & control , Infecciones por Haemophilus/clasificación , Haemophilus influenzae/clasificación , Haemophilus influenzae/efectos de los fármacos , Humanos , Relaciones Interpersonales , Masculino , Casas de Salud , Faringe/microbiología , Estaciones del Año , Tennessee/epidemiología , Precauciones UniversalesRESUMEN
Meta-hydroxyephedrine (HED) comprises four stereoisomers consisting of two enantiomeric pairs related to ephedrine and pseudoephedrine. HED is transported into adrenergic neurons and radiolabeled HED has been employed in positron emission tomography (PET) to image adrenergic neurons in vivo. To extend structure-activity analyses of binding sites within monoamine transporters and to determine which stereoisomer displayed the best selectivity for PET imaging applications, we tested the HED compounds for their abilities to inhibit [(3)H]neurotransmitter uptake into platelets, transfected cells, and chromaffin vesicles. We hypothesized that the HED compounds would be most potent at the norepinephrine transporter (NET) compared to the serotonin or dopamine transporters and that the 1R diastereomers would be more effective than 1S diastereomers. Supporting the hypotheses, all stereoisomers were most potent at the NET and the 1R,2S stereoisomer was the most potent inhibitor overall. However, the 1S,2R isomer may be preferred for PET applications because of better selectivity among the transporters and reduced neuronal recycling.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Efedrina/análogos & derivados , Efedrina/farmacología , Proteínas de Transporte de Membrana , Neuropéptidos , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Proteínas Portadoras/química , Bovinos , Membrana Celular/metabolismo , Células Cultivadas , Gránulos Cromafines/efectos de los fármacos , Gránulos Cromafines/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Estereoisomerismo , Transfección , Proteínas de Transporte Vesicular de Aminas BiógenasRESUMEN
A series of arylhydantoin derivatives modeled after the antiandrogen RU 58841 was generated to identify potential candidates for development as androgen receptor (AR) radioligands. Side-chain modified derivatives of RU 58841, suitable for labeling with either carbon-11 or radiohalogens (fluorine-18, iodine-123), were synthesized and tested for their AR binding affinities. The N-(iodopropenyl) derivative 13 (Ki = 13 nM) is a potential candidate for development as a radioiodinated AR ligand.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/metabolismo , Animales , Sitios de Unión/fisiología , Isótopos de Carbono/química , Flúor/química , Hidantoínas/síntesis química , Hidantoínas/metabolismo , Imidazoles/metabolismo , Nitrilos/metabolismo , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
4-[4, 4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-+ ++trif luoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-i odo benzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K(i) = 0.71 +/- 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5alpha-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.
Asunto(s)
Imidazoles/síntesis química , Receptores Androgénicos/metabolismo , Tionas/síntesis química , Andrógenos , Animales , Unión Competitiva , Línea Celular , Dihidrotestosterona/farmacología , Diseño de Fármacos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Técnicas In Vitro , Ligandos , Masculino , Nitrilos/química , Nitrilos/metabolismo , Nitrilos/farmacología , Próstata/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Androgénicos/fisiología , Tionas/química , Tionas/metabolismo , Tionas/farmacología , Activación TranscripcionalRESUMEN
Methods for the direct chiral chromatographic separation of the four stereoisomers of meta-hydroxyphenylpropanolamine (MHPA) on an analytical and preparative scale are described. Separations were carried out on a Crownpak CR (+) chiral column with 113 mM aqueous perchloric acid as the mobile phase. Baseline resolution of the more retained (+)-stereoisomers (1S configuration) and partial resolution of the less retained (-)-stereoisomers (1R configuration) were obtained under these chromatographic conditions. Removal of the bulk of the (1R,2S)-stereoisomer (metaraminol) from the initial crude mixture by fractional crystallization as the (+)-bitartarate salt substantially improved the peak resolution factors (Rs) of the remaining three stereoisomers. Semipreparative chromatographic resolution of the latter isomeric mixture provided milligram quantities of each stereoisomer in >97% enantiomeric excess. Subsequent recrystallization of their bitartarate or fumarate salts gave enantiomeric purities >99%.
Asunto(s)
Propanolaminas/química , Cromatografía por Intercambio Iónico , Cromatografía de Gases y Espectrometría de Masas , Metaraminol , Propanolaminas/aislamiento & purificación , EstereoisomerismoRESUMEN
The antidepressant desipramine (DMI) and its principal metabolite 2-hydroxydesipramine (HDMI) have been radiolabeled with 11C for PET studies. The normethyl precursors of DMI and HDMI were synthesized from iminodibenzyl in 35% and 11% overall yield, respectively. Direct methylation of the normethyl precursor with [11C]CH3I, followed by HPLC purification, provided [11C]DMI and [11C]HDMI in 18-30% and 15-23% decay-corrected radiochemical yields, respectively, in a 45 min synthesis time from end of bombardment. The specific activities of the two radiotracers were >1459 Ci/mmol at the end of synthesis. [11C]DMI and [11C]HDMI have potential utility as PET radiotracers for the norepinephrine transporter.
Asunto(s)
Radioisótopos de Carbono/química , Proteínas Portadoras/análisis , Desipramina/análogos & derivados , Desipramina/síntesis química , Radiofármacos/síntesis química , Simportadores , Marcaje Isotópico/métodos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Tomografía Computarizada de EmisiónRESUMEN
UNLABELLED: Alzheimer's disease is characterized by progressive cerebral cholinergic neuronal degeneration. Radiotracer analogs of benzovesamicol, which bind with high affinity to the vesamicol receptor located on the uptake transporter of acetylcholine storage vesicles, may provide an in vivo marker of cholinergic neuronal integrity. Five positional isomers of racemic iodobenzovesamicol (4'-, 5-, 6-, 7-, and 8-IBVM) were synthesized, exchange-labeled with iodine-125, and evaluated as possible in vivo markers for central cholinergic neurons. Only two isomers, 5-IBVM (5) and 6-IBVM (10), gave distribution patterns in mouse brain consistent with cholinergic innervation: striatum >> hippocampus > or = cortex > hypothalamus >> cerebellum. The 24-h tissue-to-cerebellum concentration ratios for 5-IBVM (5) were 3-4-fold higher for striatum, cortex, and hippocampus than the respective ratios for 6-IBVM (10). Neither 8-IBVM (16) nor 4'-IBVM (17) exhibited selective retention in any of the brain regions examined. In the heart, only 5-IBVM (5) exhibited an atria-to-ventricles concentration ratio consistent with high peripheral cholinergic neuronal selectivity. The 7-IBVM (14) isomer exhibited an anomalous brain distribution pattern, marked by high and prolonged retention in the five brain regions, most notably the cerebellum. This isomer was screened for binding in a series of 26 different biological assays; 7-IBVM (14) exhibited affinity only for the delta-receptor with an IC50 of approximately 30 nM. Drug-blocking studies suggested that brain retention of 7-IBVM (14) reflects high-affinity binding to both vesamicol and delta-receptors. Competitive binding studies using rat cortical homogenates gave IC50 values for binding to the vesamicol receptor of 2.5 nM for 5-IBVM (5), 4.8 nM for 6-IBVM (10), and 3.5 nM for 7-IBVM (14). Ex vivo autoradiography of rat brain after injection of (-)-5-[125I]IBVM ((-)-[125I]5) clearly delineated small cholinergic-rich areas such as basolateral amygdala, interpeduncular nucleus, and facial nuclei. Except for cortex, regional brain levels of (-)-5-[123I]IBVM ((-)-[123I]5) at 4 h exhibited a linear correlation (r2 = 0.99) with endogenous levels of choline acetyltransferase. CONCLUSION: Vesamicol receptor mapping of cholinergic nerve terminals in murine brain can be achieved with 5-IBVM (5) and less robustly with 6-IBVM (10), whereas the brain localization of 7-IBVM (14) reflects high-affinity binding to both vesamicol and delta-receptors.
Asunto(s)
Mapeo Encefálico , Encéfalo/fisiología , Fármacos Neuromusculares Despolarizantes/metabolismo , Neuronas/fisiología , Piperidinas/metabolismo , Receptores Colinérgicos/análisis , Tetrahidronaftalenos/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Autorradiografía , Unión Competitiva , Encéfalo/citología , Encéfalo/metabolismo , Femenino , Cobayas , Humanos , Radioisótopos de Yodo , Isomerismo , Ratones , Ratones Endogámicos , Fármacos Neuromusculares Despolarizantes/síntesis química , Neuronas/citología , Neuronas/metabolismo , Especificidad de Órganos , Piperidinas/síntesis química , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/síntesis químicaRESUMEN
An iodinated analog of PK11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)isoquinoline-3-carboxamide , a specific antagonist of the peripheral-type benzodiazepine receptor (omega 3), has been synthesized in three steps with an overall chemical yield of 40%. Both [123I]- and [125I]-Iodo-PK11195 have been synthesized by solid-state isotopic exchange in > 60% isolated radiochemical yield and specific activity of 233-348 mCi/mmol. Tissue distribution studies in rats indicate a high uptake of radioactivity in adrenal glands, heart, lung and kidneys, which was blocked 63-87% by preadministration of cold PK11195. Single photon emission computer tomography (SPECT) imaging of the canine heart has been accomplished with [123I]PK11195. These results suggest that [123I]PK11195 has potential as a SPECT radiotracer for studying the omega 3 receptor in humans.
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Corazón/diagnóstico por imagen , Isoquinolinas , Miocardio/metabolismo , Receptores de GABA-A/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Perros , Femenino , Técnicas In Vitro , Radioisótopos de Yodo , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Marcaje Isotópico , Masculino , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
This work explores the biomimetic potential of [18F]fluorine for hydroxy substitution in beta-phenethanolamines as a possible strategy for developing radiotracers for in vivo imaging. Stereospecific syntheses of the two model compounds (1R,2S)-1-[18F]fluoro-1-deoxyephedrine ([18F]FDE) and (1S,2S)-1-[18F]fluoro-1-deoxypseudoephedrine ([18F]FDP) were achieved in high radiochemical yield (62%, decay corrected) and high specific activity (> 2500 Ci/mmol) by reaction of [18F]fluoride ion with the appropriate chiral cyclic sulfamidate precursor. Both tracers exhibited good stability toward metabolic defluorination in vivo. High, homogeneous brain uptake (approximately 8% of injected dose) was observed after intravenous injection in mice similar to that reported for the structurally related analog [11C]methamphetamine. The 1R,2S isomer (FDE) showed a 3-fold higher concentration of radioactivity in whole brain as compared to the 1S,2S isomer (FDP). These results suggest possible employment of this strategy for chiral radiolabeling of biologically important phenethanolamines and catecholamines.
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Aminas Biogénicas/química , Aminas Biogénicas/síntesis química , Radioisótopos de Flúor , Marcaje Isotópico/métodos , Animales , Diseño de Fármacos , Femenino , Metanfetamina/análogos & derivados , Metanfetamina/síntesis química , Metanfetamina/farmacocinética , Ratones , Estereoisomerismo , Distribución TisularRESUMEN
The highly toxic curraremimetic and cholinergic neuron marker (-)-5-iodobenzovesamicol (IBVM) has been labeled with iodine-125 and iodine-123. [125I]IBVM, suitable for animal distribution and ex vivo autoradiographic studies, was synthesized by solid-state exchange; isolated yields were 65-89% with specific activities in the range of 130-200 Ci/mmol. The synthesis of no-carrier-added (-)-5-[125I]IBVM from the corresponding chiral (-)-5-(tri-n-butyltin) derivative using Na125I was evaluated using the oxidants H2O2, peracetic acid and chloramine-T. Both peracetic acid and chloramine-T gave good yields (70-95%). However, when Na123I was utilized, acceptable yields of [123I]IBVM were obtained only with chloramine-T. Use of the latter oxidant did produce 5-chlorobenzovesamicol which was eliminated during HPLC purification. After optimization of the reaction parameters, [123I]IBVM in batch sizes of 10-27 mCi, is routinely obtained with a specific activity of 30-70,000 Ci/mmol, radiochemical purity (> 97%) and chiral purity (> 98%). Isolated radiochemical yields have averaged 71% (N = 40). Distribution analyses of [125I]IBVM and [123I]IBVM in mice 4 h following intravenous administration show essentially equivalent concentrations of the two tracers in the four brain regions sampled. The exceptionally high specific activity of [123I]IBVM has made possible the evaluation of this radiotracer in humans.
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Encéfalo/metabolismo , Fibras Colinérgicas/metabolismo , Radioisótopos de Yodo/química , Fenciclidina/análogos & derivados , Piperidinas , Tetrahidronaftalenos , Animales , Cloraminas/química , Femenino , Peróxido de Hidrógeno/química , Indicadores y Reactivos/química , Marcaje Isotópico/métodos , Ratones , Ratones Endogámicos , Ácido Peracético/química , Fenciclidina/síntesis química , Fenciclidina/farmacocinética , Estereoisomerismo , Distribución Tisular , Compuestos de Tosilo/químicaRESUMEN
A series of fluorine-18 and iodine-125 labeled aryl-1,4-dialkylpiperazine analogs, derivatives of GBR 12935, were synthesized as radiotracers for positron emission tomography or single photon emission computerized tomography imaging of the brain based on their affinity for the presynaptic dopamine reuptake system. High specific activity fluorine-18 tracers were prepared by nucleophilic aromatic substitution reactions; iodine-125 tracers were prepared by isotopic exchange reactions. In vitro competitive binding studies demonstrated that iodine substitution is tolerated in the 4-position of the phenyl ring of the phenalkylpiperazine group. In vivo regional brain biodistribution studies in mice indicated no selectivity of the radioiodinated ligands for the dopamine reuptake site, with striatum/cerebellum concentration ratios of 1. Similar negative results with the new fluorine-18 derivatives demonstrated that in vivo selectivity for the dopamine reuptake site appears to be critically dependent on the carbon chain length between the piperazine ring and the solitary aromatic ring. These studies suggest that development of new radiopharmaceuticals based on the GBR 12935 structure cannot be based solely on considerations of in vitro binding affinities.
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Encéfalo/diagnóstico por imagen , Dopamina/metabolismo , Piperazinas/síntesis química , Animales , Encéfalo/metabolismo , Radioisótopos de Flúor , Radioisótopos de Yodo , Marcaje Isotópico , Ratones , Tomografía Computarizada de Emisión , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Myocardial beta adrenergic receptors play important roles in physiology and disease, but the receptors have not before been portrayed. The beta antagonist, iodocyanopindolol (ICYP), was used to develop a scintigraphic method for depicting the receptors in the living heart. Labeled with 125I, ICYP bound firmly to beta receptors in the rat heart; the data conformed to a mathematical model. In vivo saturation kinetics indicated binding sites with two affinities. Inhibition of ICYP binding by beta antagonists of different potency and different selectivity for beta-1 and beta-2 receptors produced the expected pharmacologic effects. Inhibition by lipophilic and hydrophilic antagonists gave no evidence that ICYP was appreciably bound to internalized receptors. Fractional binding by tracer quantities of (-) ICYP and (+/-) ICYP demonstrated stereospecificity. Labeled with 123I, ICYP bound to the hearts of intact dogs so that scintigraphic tomographs depicted ventricular myocardium. Small doses of beta antagonists selectively reduced the binding of ICYP to lung enabling better visualization of the heart. Thus, 123I-ICYP appears to portray the beta receptors in the living heart, and the characteristics of binding permit the development of mathematical models and lay the basis for quantifying this receptor binding.
Asunto(s)
Corazón/diagnóstico por imagen , Receptores Adrenérgicos beta , Animales , Perros , Femenino , Radioisótopos de Yodo , Yodocianopindolol , Miocardio/química , Pindolol/análogos & derivados , Pindolol/sangre , Cintigrafía , Ratas , Ratas EndogámicasRESUMEN
A convenient and efficient radiosynthesis of no-carrier-added [123I]labeled (-)iodocyanopindolol, (-)-[123I]ICYP, a high affinity beta adrenergic antagonist, is described. (-)-[123I]ICYP was synthesized by a modified chloramine-T radioiodination of (-)cyanopindolol followed by a novel reversed-phase HPLC purification that provided the radiopharmaceutical as a directly injectable solution. The total synthesis time was typically less than 45 min and provided (-)-[123I]ICYP in a 59% radiochemical yield (not corrected for decay). In view of its high affinity for the beta adrenergic receptor, (-)-[123I]ICYP is a potentially useful probe for SPECT evaluation of cardiac adrenergic receptor density.
Asunto(s)
Antagonistas Adrenérgicos beta/síntesis química , Radioisótopos de Yodo , Marcaje Isotópico/métodos , Pindolol/análogos & derivados , Antagonistas Adrenérgicos beta/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Yodocianopindolol , Pindolol/síntesis química , Pindolol/aislamiento & purificaciónRESUMEN
Carbon-11-meta-hydroxyephedrine is a new radiotracer developed for mapping the sympathetic nerves of the heart. Carbon-11-meta-hydroxyephedrine is synthesized by direct N-methylation of metaraminol with [11C]methyl iodide in dimethyl formamide/dimethyl sulfoxide and purified by semi-preparative reversed-phase HPLC. Total synthesis time is 45 min from end-of-bombardment. Carbon-11-meta-hydroxyephedrine is produced in 40%-50% corrected radiochemical yield with a specific activity of 900 Ci/mmol. Routine radiochemical and chemical purity are 95% and 98%, respectively. Biodistribution studies in rats show high myocardial uptake. Pretreatment with desipramine, a drug known to selectively block neuronal uptake, results in a 92% decrease in tracer accumulation in the myocardium. Metabolic studies in guinea pigs show less than 5% metabolites in heart tissue 30 min after intravenous injection suggesting that [11C]meta-hydroxyephedrine is suitable for kinetic modeling. These preliminary results support this new tracer as a clinical agent for neuronal imaging of the heart.
Asunto(s)
Efedrina/análogos & derivados , Corazón/inervación , Miocardio/metabolismo , Sistema Nervioso Simpático/diagnóstico por imagen , Tomografía Computarizada de Emisión , Animales , Fenómenos Químicos , Química , Desipramina/farmacología , Efedrina/síntesis química , Estudios de Evaluación como Asunto , Femenino , Cobayas , Corazón/diagnóstico por imagen , Masculino , Trazadores Radiactivos , Ratas , Ratas Endogámicas , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Distribución TisularAsunto(s)
Encéfalo/citología , Colina/metabolismo , Radioisótopos de Yodo , Neuronas/metabolismo , Fenciclidina/análogos & derivados , Piperidinas , Tetrahidronaftalenos , Acetilcolina/metabolismo , Animales , Encéfalo/metabolismo , Cerebelo/metabolismo , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Femenino , Cinética , Ratones , Estructura Molecular , Fenciclidina/síntesis química , Fenciclidina/metabolismo , Fenciclidina/farmacocinética , Estereoisomerismo , TritioRESUMEN
The false neurotransmitter metaraminol labeled with fluorine-18 has been used to noninvasively assess regional adrenergic nerve density in the canine heart. Intravenous administration of 6-[18F]fluorometaraminol (FMR) results in high, selective accumulation of radioactivity in the heart; drug blocking studies with desipramine and reserpine confirm the neuronal locus of FMR. Iodine-125 labeled metaraminol, however, shows no selective accumulation in the canine heart. Positron emission tomography (PET) analyses with FMR of closed-chest dogs bearing left ventricular neuronal defects clearly delineate the region of neuronal impairment; blood perfusion in the left ventricle wall was homogeneous as determined by [13N]NH3 tomograms. The accumulation of FMR in regionally denervated dog heart correlates closely (r = 0.88) with endogenous norepinephrine concentrations. PET-generated 18F time-activity curves demonstrate marked kinetic differences between normal and denervated myocardium. FMR/PET analysis could be used to assess the heterogeneity of sympathetic innervation in human heart disease contingent on the development of FMR with sufficiently high specific activity to clearly avoid pressor activity.