Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: control and competition studies

[18F]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic cholinergic ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anesthetized rhesus monkeys were performed to assess the in vivo behavior of this radiotracer. First, control studies (n = 11) were performed to characterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking studies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [18F]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine, an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (100 to 200 microg x kg(-1) x h(-1)) beginning 30 minutes before tracer injection (n = 7). Tracer uptake in the brain was rapid with K1 values of 0.4 to 0.6 mL x min(-1) x mL(-1) in gray matter. A model with one tissue compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. Volume of distribution (V) values, determined from functional images created by pixel-by-pixel fitting, were very similar in cortical regions, basal ganglia, and thalamus, but significantly lower (P < 0.01) in the cerebellum, consistent with the distribution of M2 cholinergic receptors. Preblocking studies with unlabeled FP-TZTP reduced V by 60% to 70% in cortical and subcortical regions. Physostigmine produced a 35% reduction in cortical specific binding (P < 0.05), consistent with increased ACh competition. The reduction in basal ganglia (12%) was significantly smaller (P < 0.05), consistent with its markedly higher AChE activity. These studies indicate that [18F]FP-TZTP should be useful for the in vivo measurement of muscarinic receptors with positron emission tomography.     

Whole-body [18F]FDG PET in the management of metastatic brain tumours

BACKGROUND: To determine its roles in the diagnosis and the systemic evaluation of metastatic brain tumours, whole-body positron emission tomography (PET) using [18F]FDG was performed in 20 consecutive patients. METHODS: All patients were thought to be suffering or needing to be differentiated from metastatic brain tumours. Nine patients had multiple brain lesions; six were older and showed a rim-enhancing lesion with surrounding oedema; seven had homogeneously enhancing periventricular lesion(s) on computed tomography (CT) and/or magnetic resonance (MR) imaging, thought to be central nervous system lymphomas. Two patients had skull mass(es) and two patients had a solid mass suspected to be, respectively, a haemorrhagic metastasis and a metastatic malignant melanoma. All of them received whole-body [18F]FDG PET and conventional systemic work-up for metastasis in order to compare the results of the two methods. RESULTS: Metastatic brain tumours were diagnosed on whole-body [18F]FDG PET in eleven patients who had extracranial and intracranial hypermetabolic lesions. In nine of these, a conventional work-up also detected primary lesions which on whole-body [18F]FDG PET were seen to be hypermetabolic foci. Systemic lymph node metastases were detected by whole-body [18F]FDG PET only in two patients and histological diagnosis was possible by biopsy of lymph nodes rather than of brain lesions. In the remaining nine patients who had only intracranial hypermetabolic foci, histological diagnosis was made by craniotomy or stereotactic biopsy. It was confirmed that seven of nine patients were suffering from a primary brain tumour and two from metastatic carcinoma. None of the nine showed evidence of systemic cancer on conventional work-up. Histological diagnoses of the primary brain tumours were four cases of primary central nervous system lymphoma and one each of multifocal glioblastoma, Ewing's sarcoma, and cavernous angioma. Patients felt no discomfort during the whole-body [18F]FDG PET procedure and there were no complications. The false negative rate in [18F]FDG PET and in conventional work-up was 15.4% and 30.7% respectively. There were no false positives on either [18F]FDG PET or conventional work-up. CONCLUSION: It is suggested that whole-body [18F]FDG PET is a safe, reliable, and convenient method for the diagnosis and systemic evaluation of patients thought to be suffering or needing to be differentiated from a metastatic brain tumour.     

Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson's disease

The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on striatal uptake of 6-[18F]fluoro-L-dopa (FDOPA) was studied with PET both without and with entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k3R0), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (Ki) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the Ki remained virtually unchanged. Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.     

The crystal and molecular structure of a valinomycin analogue cyclo[(D-Val-L-Lac-L-Ala-D-Hyi)2(D-Val-L-Lac-L-Val-D-Hyi)]. H2O(C50H82N6 O18.H2O)

The crystal and molecular structure of the valinomycin analogue, cyclo[(D-Val-L-Lac-L-Ala-D-Hyi)2(D-Val-L-Lac-L-Val-D-Hyi)] has been solved by x-ray direct methods using the "Shake and Bake" procedure. The crystals, grown from a mixture of octane/CH2Cl2, belong to space group P2(1) (Z = 4) with cell parameters a = 10.29, b = 32.08, c = 18.73 A, beta = 97.05 degrees, and contain two molecules per asymmetric unit. After anisotropic refinement the standard reliability factor was Rl = 0.058. The conformations of both independent molecules is similar to that observed for isoleucinomycin, cyclo[-(D-Ile-L-Lac-L-Ile-D-Hyi)3] [V. Z. Pletnev et al. (1980) Biopolymers, Vol. 19, pp. 1517-1534]. The structure has an asymmetric conformation stabilized by six intramolecular H bonds, five bonds being of the 4-->1 type and one bond being of the 5-->1 type. One water molecule is caged in the internal cavity of each cyclodepsipeptide. This conformation could represent an intermediate state between free and complexed forms of valinomycin.     

Sources of error in tissue and tumor measurements of 5-[18F]fluorouracil

Central to the assessment of variability of pharmacokinetic parameters is knowledge of bias and variability of the measurement technique, preventing observed differences from being ascribed inappropriate significance. This article presents an evaluation of sources of error in the measurement of normal tissue and tumor pharmacokinetics using 18F-labeled 5-fluorouracil (FU) and PET. METHODS: A standard approach to data acquisition, processing and analysis was developed using a PET scanner, filtered backprojection reconstruction and region of interest analysis. Fourteen tracer 5-[18F]FU patient studies and a phantom study were completed, with 4 of the patient studies repeated 1 wk later. These data allowed evaluation of the overall reproducibility of the technique and the components of measurement variability due to tissue sampling. The effect of reconstruction technique and sampling region size on quantification was assessed using phantom data. RESULTS: All measured radioactivity versus time curves were tissue specific. Week-to-week variability in the area under this curve (representing combined physiological and measurement difference) was -3% to +15% for liver and -9% to -16% for spleen and kidney. Metastasis variability was greatest at -20%. Visual and computer realignment of the second paired study produced similar results. Interobserver effects were small compared to differences between studies. CONCLUSION: These results confirm the feasibility of using PET as a pharmacokinetic tool for 5-[18F]FU studies. Although overall experimental error (i.e., random variation in data acquisition, processing and analysis) was low, constraints in data interpretation emerged.     

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.     

Simultaneous measurement of [18F]FDOPA metabolism and cerebral blood flow in newborn piglets

Three diets containing either borage oil (BO) and southern hemisphere fish oil Marinol (MO), or BO and tuna orbital oil (TO), or a northern hemisphere fish oil (FO) were fed to duplicate groups of turbot (Scophthalmus maximus) of initial mean weight 1.2 g for a period of 12 weeks. The BO/MO and BO/TO diets were enriched in gamma-linolenic (18:3n-6, GLA) and eicosapentaenoic (20:5n-3, EPA) acids, and GLA and docosahexaenoic acid (22:6n-3, DHA), respectively. No differences were observed in final weights or growth rates, either between duplicate tanks or between dietary treatments. Half of the FO-fed fish sampled showed a histopathological lesion indicative of lipoid liver degeneration while the other treatments only showed a slight incidence of the same pathology. The fatty acid compositions of carcass and tissues broadly reflected the dietary input. In general, fish fed the BO/MO diet had increased levels of 18:2n-6, 18:3n-6, 20:3n-6 and 20:5n-3, but a lower level of 22:6n-3, compared to fish fed FO. In fish fed the BO/TO diet, levels of 18:2n-6, 18:3n-6, 20:3n-6 and 20:4n-6 were increased while levels of 20:5n-3 and 22:5n-3 were reduced, compared to fish fed FO. Concentrations of thromboxanes B (TXB) and leukotrienes B (LTB), derived from 20:4n-6 and 20:5n-3, were measured in plasma and stimulated blood cells. Levels of TXB2 were greatest in fish fed the BO/TO diet compared to both other treatments, while LTB4 was decreased in fish fed the BO/MO diet compared to both other treatments. In a stress test which involved anaesthesia followed by measurement of recovery times, fish fed the BO/MO diet had significantly lower recovery times compared to fish fed the FO diet.     

Syntheses and Crystal Structure of Nine-Coordinate Mononuclear Na[ EuⅢ (edta)(H2O)3] · 4H2O and Binuclear Na4[Eu2Ⅲ(Httha)2]·10H2O Complexes

The crystal and molecular structures of the Na[Eu Ⅲ (edta) ( H2 O) 3] · 4H2O ( edta = ethylenediaminetetraacetic acid) and Na4[Eu2Ⅲ (Httha)2] · 10H2 O ( ttha = triethylenetetraminehexaacetic acid) complexes were determined by single-crystal X-ray structure analyses.The crystal of Na[ EuⅢ (edta) (H2O)3] · 4H2O belongs to orthorhombic crystal system and Fdd2 space group.The crystal data are as follows: a = 1.9415 (15)nm, b = 3.544(3 )nm, c = 1.203(9)nm, V = 8.327(5)nm3, Z = 16, M = 589.27, Dc= 1.880 g· cm-3, μ= 3.108mm-1 and F(000) = 4704.The final R and wR values are 0.0312 and 0.0750 for 2091[I ＞ 2.0σ (I)] reflections, and 0.0344and 0.0766 for all 3932 unique reflections, respectively.The[EuⅢ (edta) (H2O) 3] - anion has a nine-coordinate pseudo-monocapped square antiprismatic structure in which the nine coordinate atoms, two N and seven O, are from one edta ligand and three water molecules.The crystal of Na4[Eu2Ⅲ (Httha)2] · 10H2O belongs to orthorhombic system and Pccn space group.The crystal data are as follows: a = 2.610(3)nm, b = 2.089(3)nm, c = 2.239(3)nm, V =12.208 ( 28 ) nm3, Z = 8, M = 1548.92, Dc= 1.686g·cm-3,μ = 2.115 mm-1andF(000) = 6272.Thefinal R and wR are 0.0625 and 0.1091 for 9834[I ＞ 2.0σ(I)] reflections, and 0.1608 and 0.1471 for all 37818 unique reflections, respectively.The whole complex molecule is composed of two close parts in which each one has a nine-coordinate structure with distorted monocapped square antiprismatic prism.The ttha ligand in the[Eu2Ⅲ (Httha)2] 4- anion coordinates to one Eu Ⅲ ion with three N atoms and four O atoms and to the other Eu Ⅲ ion with two O atoms.     

化合物Rb[(H2Ssal)(H2O)]的合成与表征

采用碳酸铷和磺基水杨酸在水溶液中直接反应，合成了新的Rb—H2Ssal的化合物，采用元素分析和原子吸收法确定新化合物的组成为Rb[（H2Ssal)（H2O)]，用X射线粉末衍射法，FT-IR，Raman光谱法对新化合物进行了物理化学表征。     

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects

BACKGROUND: In the FRISC trial, dalteparin 120 IU/kg body weight twice daily for unstable coronary artery disease was safe and reduced the risk of new coronary events. This risk reduction was maintained during the following extended treatment with a fixed dose of 7500 IU dalteparin once daily. METHODS AND RESULTS: Minor bleeding was more frequent in women compared with men: relative risk (CI) 2.88 (1.78 to 4.67) during the weight-adjusted and 2.36 (1.37 to 2.63) during the fixed dose treatment. The anti-Xa activity determined in samples (n = 175) obtained during the acute phase treatment was higher in women compared with men (P <.001) and in nonsmokers compared with smokers (<.001) in multiple regression analysis. Also, during the fixed-dose treatment (n = 131) an independent relation between anti-Xa activity and sex (P <.001), but not smoking habits, persisted. CONCLUSION: To improve future low-molecular-weight heparin dose regimens for the treatment of acute coronary syndromes, it might be important to consider the influence of sex and smoking habits.     

Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy

We assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and 16alpha-[18F]fluoro-17beta-estradiol (FES) in women with breast cancer for predicting response to systemic therapy. Results of FES-PET were correlated with estrogen receptor (ER) status. Forty-three women with locally advanced or metastatic breast cancer underwent FDG-PET and FES-PET prior to institution of systemic therapy. All patients had measurable disease and had tumors submitted for ER determination. Cancers were considered functionally hormone sensitive if the standardized uptake value of the lesion on FES-PET was >/=1.0 (FES+) and hormone resistant if the standardized uptake value was <1.0 (FES-). Information obtained by FES-PET was compared with the results of ER assays. The tumor response to chemotherapy and hormonal therapy was correlated with intensity of uptake by both FDG-PET and FES-PET. The ER status of the breast cancers was negative (ER-) in 20 patients, positive (ER+) in 21 patients, and unknown in 2 patients. All 20 of the ER- tumors were also FES-. However, of the 21 ER+ tumors, 16 were FES+ and 5 were FES-. Thirty patients were treated initially with chemotherapy, and 21 (70%) demonstrated objective responses. We were unable to correlate the response to chemotherapy with information obtained by FDG-PET or FES-PET. Thirteen patients were treated with hormone therapy, and 8 (61%) responded to that therapy. Only 1 of the 5 patients whose tumors were ER+ but FES- received hormone therapy, and this treatment resulted in disease stabilization only. Multiple sites of disease were assessed by FES-PET in 17 patients with metastatic breast cancer. Functional hormone sensitivity, defined by FES-PET, was concordant with multiple lesions in 13 (76%). Ten patients with locally advanced breast cancer developed recurrent disease. The initial site of recurrence was the breast in 5 patients. Of the 5 patients with systemic recurrence, 4 had disease detected at the site of recurrence on the pretreatment FDG-PET study but not detected on pretreatment computed tomography. In our experience, FDG-PET imaging is more sensitive than conventional imaging methods, including computed tomography, in staging women with breast cancer. When compared with the in vitro assay of ER status, FES-PET has an apparent sensitivity of 76% and specificity of 100%. Our finding of a subset of patients who have tumors that are ER+ and FES- suggests that the functional assessment of hormone sensitivity by PET imaging can identify patients with ER+ disease whose tumors are likely to be hormone refractory.     

Evaluation of compartmental and spectral analysis models of [18F]FDG kinetics for heart and brain studies with PET

Various models have been proposed to quantitate from [18F]-Fluoro-Deoxy-Glucose ([18F]FDG) positron emission tomography (PET) data glucose regional metabolic rate. We evaluate here four models, a three-rate constants (3K) model, a four-rate constants (4K) model, an heterogeneous model (TH) and a spectral analysis (SA) model. The data base consists of [18F]FDG dynamic data obtained in the myocardium and brain gray and white matter. All models were identified by nonlinear weighted least squares with weights chosen optimally. We show that: 1) 3K and 4K models are indistinguishable in terms of parsimony criteria and choice should be made on parameter precision and physiological plausibility; in the gray matter a more complex model than the 3K one is resolvable; 2) the TH model is resolvable in the gray but not in the white matter; 3) the classic SA approach has some unnecessary hypotheses built in and can be in principle misleading; we propose here a new SA model which is more theoretically sound; 4) this new SA approach supports the use of a 3K model in the heart with a 60 min experimental period; it also indicates that heterogeneity in the brain is modest in the white matter; 5) [18F]FDG fractional uptake estimates of the four models are very close in the heart, but not in the brain; 6) a higher than 60 min experimental time is preferable for brain studies.     

Lymphoma: role of whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET in nodal staging

PURPOSE: To compare 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) in primary nodal staging of malignant lymphoma. MATERIALS AND METHODS: Sixty consecutive patients with untreated, histopathologically proved malignant lymphoma (aged 7-72 years; 33 with non-Hodgkin lymphoma, 27 with Hodgkin disease) underwent FDG PET and contrast material-enhanced CT for nodal staging. Lymph node regions identified at both CT and PET were regarded as actual locations of disease. Discordant results were verified with biopsy or clinical follow-up whenever possible. RESULTS: One hundred sixty of 740 evaluated lymph node regions were identified as diseased at both CT and PET. Of the 25 additional regions seen with PET, seven were true-positive; two, false-positive; and 16, unresolved. CT showed six additional disease manifestations; three were false-positive, and three were unresolved. Staging was changed in the four patients with the seven confirmed additional PET findings: from stage I to II in one patient and from stage II to III in three patients. Staging was changed from stage II to I in one of the three patients with false-positive CT findings. CONCLUSION: FDG PET may be more accurate for detecting nodal lymphoma than incremental CT.     

Synthesis and Structural Determination of Eight Coordinate NH_4[Yb(Ⅲ)(Cydta)(H_2O)_2]·5H_2O

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Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging

The impact of simultaneous environmental stresses on plants and how they respond to combined stresses compared with single stresses is largely unclear. By using a transgene (RD29A-LUC) consisting of the firefly luciferase coding sequence (LUC) driven by the stress-responsive RD29A promoter, we investigated the interactive effects of temperature, osmotic stress, and the phytohormone abscisic acid (ABA) in the regulation of gene expression in Arabidopsis seedlings. Results indicated that both positive and negative interactions exist among the studied stress factors in regulating gene expression. At a normal growth temperature (22 degrees C), osmotic stress and ABA act synergistically to induce the transgene expression. Low temperature inhibits the response to osmotic stress or to combined treatment of osmotic stress and ABA, whereas low temperature and ABA treatments are additive in inducing transgene expression. Although high temperature alone does not activate the transgene, it significantly amplifies the effects of ABA and osmotic stress. The effect of multiple stresses in the regulation of RD29A-LUC expression in signal transduction mutants was also studied. The results are discussed in the context of cold and osmotic stress signal transduction pathways.     

Reliability of a simple non-invasive method for the evaluation of 5-HT2 receptors using [18F]-setoperone PET imaging

This study was designed to determine the effects of oral administration of the copper(II) complex of amino acids, on gastric lesions induced by ethanol in rats and the possible mechanism(s) of protection. The copper(II) complex of L-tryptophan and L-phenylalanine is reported as the most effective in reducing ulcer numbers as well as ulcer severity of the many amino acid complexes studied. We investigated the role of PGE2 and nitric oxide (NO) in the protection afforded by Cu(II)(L-Trp)(L-Phe) against ethanol-induced damage. The involvement of endogenous eicosanoids and NO was evaluated with the respective inhibitors of prostaglandin and NO synthesis, indomethacin and NG-nitro-L-arginine (L-NNA). Ex vivo PGE2 accumulation in the rat gastric mucosa has also been determined. Pretreatment with indomethacin only partially counteracted the protective activity of Cu(II)(L-Trp)(L-Phe). L-NNA did not attenuate the protection by Cu(II)(L-Trp)(L-Phe), which was reduced but not prevented by indomethacin, suggesting that prostanoids contribute to the Cu(II)(L-Trp)(L-Phe) protective effect, together with some mechanism(s) other than NO synthesis.     

Relationship between liver function and splenic blood flow (quantitative measurement of splenic blood flow with H2(15)O and a dynamic state method: 2)

A case is reported of persistent primitive trigeminal artery associated with recurrent facial pain and noncomitant strabismus by partial ipsilateral oculomotor palsy. Transcranial Doppler disclosed indirectly persistent carotid-basilar anastomosis. CT and angiography allowed complete diagnosis excluding a posterior communicating artery aneurysm, a Tolosa-Hunt syndrome and an ophthalmoplegic migraine. Steroid therapy is recommended treatment. Surgery should be considered when symptoms are intractable to medical therapy.     

稀土杂多配合物K15[Ce (BW11O39)2]·17H2O与BSA的相互作用

利用紫外光谱,以曙红Y(Eosin Y)为探针,考察了稀土杂多配合物K15[Ce(BW11O39)2]·17H2O与牛血清白蛋白(BSA)间的作用,K15[Ce(BW11O39)2]·17H2O与Eosin Y在BSA上有竞争结合,表面活性剂对两者间的竞争结合有增敏作用;并利用荧光光谱直接考察了K15[Ce(BW11O39)2]·17H2O与BSA的相互作用及其对BSA构象的影响.     

稀土配合物[REL3(4-picNO)H2O]的合成与表征

合成了2,3-二氯异丁酸根和4-甲基吡啶氮氧化物稀土三元配合物(RE=La、Ce、Pr、Nd、Sm、Eu).通过元素分析、红外、紫外、荧光、X射线粉末衍射、XPS、热分析以及摩尔电导等分析手段,确定了配合物的组成为[REL3(4-picNO)H2O](L= CH3C2H2Cl2COO -),并对它们的性质进行了讨论.     

[Nd(PW11O39)(H2O)3](H2bpy)2·4H2O的水热合成及晶体结构

采用水热法合成稀土无机有机杂化化合物[Nd(PW11O39)(H2O)3 ](H2bpy)2·4H2O.采用NdCl3·6H2O,(NH4)3PW12O40·3H2O, 4,4'-联吡啶(bpy),和去离子水(摩尔比为4∶1∶4∶3900, pH=6)在130℃下进行水热反应3天,得到标题化合物的紫红色块状晶体,并进行了红外光谱分析,元素分析.用单晶X射线衍射法测得晶体结构,属三斜晶系,空间群为P-1,晶胞参数为a=1.18824(9) nm,b =1.35707(10)nm,c=1.77691(13)nm,α=71.551(2)°,β=82.478(2)°,γ=80.568(2)°.该晶体由无机的共价链∞1[Nd(PW11O39)(H2O)3]4- 和有机的二质子化的4,4'-联吡啶(H2bpy)2 及结晶水分子堆积而成的, 是一个新的稀土磷钨酸盐无机有机杂化化合物.