RESUMEN
In this study, in vivo evaluation in mice and rabbits of [123I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide ([123I]-BPB), a potential radioligand for visualisation of the sigma receptor by single photon emission computed tomography (SPECT), is reported. The compound possesses appropriate lipophilicity (log P=2.2) and binds sigma-1 and sigma-2 receptors (pKi=6.51 and 6.79, respectively). In mice, this new radioiodinated tracer exhibited high brain uptake (4.99% ID/g tissue at 10 min postinjection) and saturable binding (3.06% ID/g tissue at 10 min postinjection) as determined by pretreatment with unlabeled [123I]-BPB. A metabolite study demonstrated no (less than 5%) labeled metabolites in the brain. In rabbits, regional brain distribution was investigated and the tracer displayed high, homogeneous central nervous system uptake. Selectivity was assessed by competition experiments with known sigma ligands. Metabolite analysis showed no (less than 8%) labeled metabolites in the rabbit brain. In conclusion, our findings indicate that [123I]-BPB is not a suitable tracer for visualisation of D3 receptors while its potential for sigma receptor imaging is severely hampered by its affinity for dopamine receptors.
Asunto(s)
Benzamidas , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Piperazinas , Receptores sigma/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Benzamidas/farmacocinética , Estudios de Factibilidad , Masculino , Tasa de Depuración Metabólica , Ratones , Especificidad de Órganos , Piperazinas/farmacocinética , Conejos , Radiofármacos/farmacocinética , Especificidad de la Especie , Distribución TisularRESUMEN
The development of imaging methods to measure changes in NMDA ion channel activation would provide a powerful means to probe the mechanisms of drugs and device based treatments (e.g., ECT) thought to alter glutamate neurotransmission. To provide a potential NMDA/PCP receptor PET tracer, we synthesized the radioligand [11C]GMOM (ki = 5.2 +/-0.3 nM; log P = 2.34) and evaluated this ligand in vivo in awake male rats and isoflurane anesthetized baboons. In rats, the regional brain uptake of [11C]GMOM ranged from 0.75+/-0.13% ID/g in the medulla and pons to 1.15+/-0.17% ID/g in the occipital cortex. MK801 (1 mg/kg i.v.) significantly reduced (24-28%) [11C]GMOM uptake in all regions. D-serine (10 mg/kg i.v.) increased [11C]GMOM %ID/g values in all regions (10-24%) reaching significance in the frontal cortex and cerebellum only. The NR2B ligand RO 25-6981 (10 mg/kg i.v.) reduced [11C]GMOM uptake significantly (24-38%) in all regions except for the cerebellum and striatum. Blood activity was 0.11+/-0.03 %ID/g in the controls group and did not vary significantly across groups. PET imaging in isoflurane-anesthetized baboons with high specific activity [11C]GMOM provided fairly uniform regional brain distribution volume (VT) values (12.8-17.1 ml g(-1)). MK801 (0.5 mg/kg, i.v., n = 1, and 1.0 mg/kg, i.v., n = 1) did not significantly alter regional VT values, indicating a lack of saturable binding. However, the potential confounding effects associated with ketamine induction of anesthesia along with isoflurane maintenance must be considered because both agents are known to reduce NMDA ion channel activation. Future and carefully designed studies, presumably utilizing an optimized NMDA/PCP site tracer, will be carried out to further explore these hypotheses. We conclude that, even though [11C]GMOM is not an optimized PCP site radiotracer, its binding is altered in vivo in awake rats as expected by modulation of NMDA ion channel activity by MK801, D-serine or RO 25-6981. The development of higher affinity NMDA/PCP site radioligands is in progress.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Guanidinas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Fenciclidina/metabolismo , Animales , Estudios de Factibilidad , Guanidinas/química , Masculino , Tasa de Depuración Metabólica , Especificidad de Órganos , Papio , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas , Distribución TisularRESUMEN
Several studies have demonstrated a positive correlation between tumor progression and expression of extracellular proteinases such as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 have become attractive targets for cancer research because of their increased expression in human malignant tumor tissues of various organs, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'-[(123)I]iodo-biphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid (9) and 2-(4'-[(123)I]iodo-biphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionamide (11) were synthesized by electrophilic aromatic substitution of the tributylstannyl derivatives and resulted in radiochemical yields of 60% +/- 5% (n = 3) and 70% +/- 5% (n = 6), respectively. In vitro zymography and enzyme assays showed high inhibition capacities of the inhibitors on gelatinases. In vivo biodistribution showed no long-term accumulation in organs and the possibility to accumulate in the tumor. These results warrant further studies of radioiodinated carboxylic and hydroxamic MMP inhibitor tracers as potential SPECT tumor imaging agents.
Asunto(s)
Amidas/farmacocinética , Radioisótopos de Yodo/farmacocinética , Metaloproteinasas de la Matriz/metabolismo , Neoplasias/metabolismo , Propionatos/farmacocinética , Radiofármacos/farmacocinética , Amidas/química , Animales , Biomarcadores de Tumor/metabolismo , Estudios de Factibilidad , Radioisótopos de Yodo/química , Marcaje Isotópico/métodos , Inhibidores de la Metaloproteinasa de la Matriz , Tasa de Depuración Metabólica , Ratones , Neoplasias/diagnóstico por imagen , Especificidad de Órganos , Propionatos/química , Cintigrafía , Radiofármacos/síntesis química , Distribución TisularRESUMEN
OBJECTIVES: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [(123)I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [(123)I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings. METHODS: Ten AD and 9 control subjects were included. [(123)I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated. RESULTS: The mean [(123)I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [(123)I]iodo-PK11195 uptake and cognitive deficits. CONCLUSIONS: [(123)I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of microglial inflammation in AD.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Encefalitis/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Radioisótopos de Yodo , Isoquinolinas , Microglía/diagnóstico por imagen , Neocórtex/diagnóstico por imagen , Receptores de GABA-A/fisiología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Mapeo Encefálico , Dominancia Cerebral/fisiología , Encefalitis/inmunología , Encefalitis/patología , Femenino , Humanos , Masculino , Escala del Estado Mental , Microglía/inmunología , Microglía/patología , Persona de Mediana Edad , Neocórtex/inmunología , Neocórtex/patología , Proyectos Piloto , Ensayo de Unión Radioligante , Valores de Referencia , Regulación hacia Arriba/fisiologíaRESUMEN
The synthesis and evaluation of [(11)C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [(11)C] methyl iodide afforded the title compound [(11)C]zolpidem in a yield of 19.19 +/- 3.23% in 41 +/- 2 min in specific activities of 0.995-1.19 Ci/micromol (1.115 +/- 0.105 Ci/micromol) (n = 3; decay corrected, EOB). The amount of radioactivity in the brain after tail vein injection in male Wistar rats was low, and the regional distribution was homogeneous and not consistent with the known distribution of the central benzodiazepine receptors. The frontal cortex/cerebellum ratio was not significantly greater than one (1.007 +/- 0.266 at 5 min) and did not increase from 5 to 40 min post-injection. A PET brain imaging study in one baboon confirmed the results obtained in rats. Therefore, it can be concluded that [(11)C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.
Asunto(s)
Agonistas del GABA/síntesis química , Piridinas/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Agonistas del GABA/farmacocinética , Agonistas del GABA/farmacología , Masculino , Papio , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Wistar , Distribución Tisular , Tomografía Computarizada de Emisión , ZolpidemRESUMEN
UNLABELLED: Indirect estimations of brain neurotransmitters in patients with anorexia nervosa (AN) and low weight have demonstrated a reduction in brain serotonin (5-HT) turnover in general and led to hypotheses about dysfunction in the 5-HT(2a) receptor system. It was our aim to investigate the central 5-HT(2a) receptor binding index using SPECT brain imaging. METHODS: The 5-HT(2a) receptors of low-weight patients with AN were studied by means of the highly specific radioiodinated 5-HT(2a) receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide or (123)I-5-I-R91150. Fifteen patients with clinical diagnoses of AN and 11 age-matched healthy volunteers received intravenous injections of 185 MBq (123)I-5-I-R91150 and were scanned with high-resolution brain SPECT. RESULTS: Compared with healthy volunteers, patients with AN had a significantly reduced 5-HT(2a) binding index in the left frontal cortex, the left and right parietal cortex, and the left and right occipital cortex. A significant left-right asymmetry was noted in the frontal cortex (left < right). CONCLUSION: These results are in accordance with diminished metabolic and perfusion of frontal and parietal cortices reported in recent neuroimaging studies and imply localized disturbed serotonergic function. The data are discussed in the light of possible confounding factors related to the low-weight AN status. A regional cortical reduction in 5-HT(2a) binding index is not likely to be caused by a general reduction in serotonergic function due to the possible confounding factors. Suggestions for further research are given.
Asunto(s)
Corteza Cerebral/metabolismo , Radioisótopos de Yodo/farmacocinética , Piperidinas/farmacocinética , Receptores de Serotonina/metabolismo , Adolescente , Adulto , Anorexia Nerviosa , Corteza Cerebral/diagnóstico por imagen , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Humanos , Masculino , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/metabolismo , Radiofármacos/farmacocinética , Receptor de Serotonina 5-HT2A , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
A series of N,N'-diphenyl and N-naphthyl-N'-phenyl guanidine derivatives was synthesized as potential N-methyl-D-aspartate (NMDA) receptor positron emission tomography (PET) ligands. The affinity of the different compounds was determined using in vitro receptor binding assays, and their log P values were estimated using HPLC analysis. The effect of N'-3 and N'-3,5 substitution on affinity and lipophilicity was examined. The K(i) values ranged from 1.87 to 839nM, while log P values between 1.22 and 2.88 were observed.