Receptor alterations in manganese intoxicated monkeys

The density of four different receptors and one marker of dopamine uptake sites were analyzed in monkey brains after manganese exposure (0.1 g manganese per month during 26 months, a dose comparable to that workers might inhale in dusty environments) by means of quantitative receptor autoradiography. The binding of³H-mazindol to the dopamine uptake sites was reduced by 75% in both the head of the caudate nucleus and putamen, while it remained unchanged in the other regions analyzed. The binding of the D1 receptor ligand³H-SCH 23 390 was reduced about 45% in the same areas as mazindol binding, while the density of D2 receptors was unaffected. The muscarinic acetylcholine receptors as well as GABA_A receptors remained also unchanged in all brain areas analyzed after manganese exposure. Thus the dopaminergic neurons must be considered to be vulnerable to manganese concentrations attainable in the work environment. Our results also indicate that postsynaptic structures containing D1 receptors are sensitive while cells containing D2 receptors are either spared or compensated for by up-regulation of the number of receptors on remaining sites.     

Drug distribution in dog brain studied by positron emission tomography

We used positron emission tomography to monitor the distribution of radioactivity in dog brain and muscle following i.v. administration of 11C-labelled antipyrine, imipramine, and quinidine. Twenty-five sequential scans of a transaxial slice of the head were performed within 90 min; radioactivity in plasma was measured in a gamma-counter. Following i.v. injection of [11C]antipyrine (50 mg kg-1; 9-68 mCi; n = 10), the decay of plasma activity was accompanied by rapid uptake in brain and variable uptake in muscle, immediately followed by a redistribution leading to equalization of the radioactivity in the tissues. Administration of [11C]imipramine (4 mg kg-1; 30-110 mCi; n = 8) was followed by a rapid build-up of a sustained gradient between high brain, and low plasma and muscle radioactivity. After i.v. injection of [11C]quinidine (1 mg kg-1; 11-87 mCi; n = 10), radioactivity in brain was low, with higher activity in plasma and muscle throughout the experiment. Positron emission tomography thus revealed for each drug a distinct pattern of distribution consistent with established properties of the compounds. This technique seems promising for the study of early drug distribution, notwithstanding certain limitations.     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.     

Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels

The percentage occupation of striatal dopamine D₂ receptors has been evaluated in 25 patients using⁷⁶Br-bromospiperone positron emission tomography (PET) and prolactin plasma levels (PRL) during oral neuroleptic treatment (11 studies), 1–90 days following discontinuation of such treatment (16 studies), and 1–120 days after last intramuscular administration of depot neuroleptics (nine studies). The PET-estimated occupation was highly significantly correlated in a sigmoîd-like fashion to the logarithm of the chlorpromazine-equivalent dose of oral neuroleptics (suggesting a strict dose-occupation relationship during oral neuroleptic treatment and supporting the D₂-mediated hypothesis of neuroleptic action), while PRL was weakly related to daily dosage. Following withdrawal, return to normal receptor availability, as estimated by PET, occurred within 5–15 days (suggesting that protracted effects of neuroleptics after withdrawal are not due to sustained D₂ receptor occupation), but PRL values fell even more rapidly. Efficient treatment with depot neuroleptics resulted in marked PET-estimated D₂ receptor occupation, stable over the whole 4-week drug-administration interval, suggesting that longer intervals could be appropriate; PRL values bore no relationship to PET-estimated occupation, indicating variable intersubject tolerance to neuro-endocrine dopamine blockade. Overall, PET was much more sensitive than PRL to estimate striatal D₂ receptor occupation in vivo.Presented in part at the 5th International Meeting on Clinical Pharmacology in Psychiatry, Tromsø, Norway, June 26–29, 1988     

Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography

Benzodiazepine receptor occupancy in the brain following oral administration of clonazepam (CZP) with a dose of 30 g/kg in six healthy young men and a further dose of 50 g/kg in one of the subjects was estimated by carbon-11 labeled Ro15-1788 and positron emission tomography (PET). The effects of CZP on the latency of auditory event-related potentials (P300) were also studied. Overall brain ¹¹C uptake was depressed and the % inhibition of ¹¹C uptake in the gray matter of the brain at 30 min after [¹¹C]Ro15-1788 injection was 15.3–23.5% (mean, n=6) following 30 g/kg CZP when compared with that in the control experiment without any previous treatment. The ¹¹C uptake in the cerebral cortex in the subject who received both doses decreased in a dose-related manner after 30 g/kg and 50 g/kg CZP. The P300 latency was prolonged significantly by 30 g/kg CZP [31.6±16.3 ms (mean±SD, n=6), P<0.05]. The P300 latency in the same subject was prolonged in a dose-related manner by 30 g/kg and 50 g/kg CZP. The technique using [¹¹C]Ro15-1788 and PET permits comparison of the pharmacological effects with the percentage of receptor sites which benzodiazepines occupy in the human brain. P300 also seems to be useful to investigate the pharmacological effects of benzodiazepines.     

心肌磁共振显像与核素心肌灌注显像测定左心功能的对比研究

目的评价心肌磁共振显像(MRI)和门控核素心肌灌注显像(SPECT)检测急性心肌梗死(AMI)患者左心室功能的应用价值。方法AMI患者23例,分别于1周内行MRI和SPECT检查,测定左室舒张末期容积(EDV)、收缩末期容积(ESV)和射血分数(EF),将MRI检测结果作为标准,并与SPECT结果比较,行相关分析及一致性检验。结果MRI采用多层Simpson法,图像空间分辨率高,可以准确划分血池和心肌的界限。SPECT较MRI低估左室容积EDV(16±27)mL,ESV(8±21)mL,EF值两者大致相等。经相关分析,SPECT与MRI所测EDV、ESV、EF相关系数分别为0.79、0.84、0.84(P均<0.01)。经Bland-Altman一致性检验,SPECT与MRI所测左室容积及EF有等价性。结论MRI检测心功能准确、可靠。SPECT与MRI具有等价性。     

Age-related changes in human D1 dopamine receptors measured by positron emission tomography

The effects of age on the binding parameters of¹¹C-SCH23390, the highly selective ligand for central D1 dopamine receptors, at specific binding sites in the brain were studied. Seventeen healthy male volunteers (20–72 years old) participated. Regional radioactivity in the brain was followed for 40 min by positron emission tomography (PET). A high accumulation of radioactivity was observed in the striatum and there was a conspicuous accumulation in the neocortex. A two-compartment model was used to obtain quantitative estimates of rate constants of association (k₃) and dissociation (k₄). The binding potential (k₃/k₄) of the dopamine D1 receptors in the striatum and frontal cortex decreased by 35% and 39%, respectively, with age. The value of k₃ decreased by 58% in the striatum and 83% in the frontal cortex, whereas the value of k₄ decreased by 35% in the striatum and 72% in the frontal cortex with age.     

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography

Positron emission tomography (PET) was used to determine regional brain glucose metabolism in schizophrenic patients (n=17) before and during neuroleptic treatment. The patients had not been treated with neuroleptics for at least 3 weeks before the first study. All suffered from acute psychotic symptoms and were hospitalized to obtain neuroleptic treatment. After determination of regional brain metabolism without neuroleptic treatment, 11 patients were treated with sulpiride (800 mg/day) and 6 patients were treated with chlorpromazine (400 mg/day) over 5–6 weeks before the second PET investigation. The control group consisted of seven healthy male volunteers, also investigated twice 5 weeks apart. The PET investigation was made with the subject in a resting state. The tracer was uniformly labelled ¹¹C-glucose. The metabolism was determined bilaterally in 15 brain regions cortical, as well as central regions. Metabolic rates differed among the groups. The sulpiride group had lower metabolic rates than the controls and the schizophrenic patients later treated with chlorpromazine. The sulpiride group, in which absolute metabolic rates were determined, were clinically more autistic and chronic than the chlorpromazine group. It was proposed that these facts could explain the lower metabolic rates in the sulpiride group. A significant change in metabolism in relation to drug treatment was only found in one brain region. The selective D2-receptor antagonist sulpiride increased the metabolic rate in the right lentiform nucleus in comparison with the patients treated with chlorpromazine and the controls. Likewise, relative metabolic rates were increased only in the right lentiform nucleus. Negative correlations between intensity of clinical symptoms and metabolism indicated that emotional tone and drive were related to brain metabolism. No correlations were found between drug concentrations and metabolism or clinical symptoms.     

Purification of [18F]-fluoro-L-thymidine ([18F]-FLT) for positron emission tomography imaging

3'-Deoxy-3'-[18F]fluorothymidine ([18F]-FLT) has recently been described as a positron emission tomography (PET) radiopharmaceutical for visualizing cellular proliferation in vivo. All published radiosyntheses of [18F]-FLT provide crude products that must be purified before injection to human. This study describes a reliable purification procedure for [18F]-FLT. It is based on HPLC. In 17.9+/-0.5 min, pure [18F]-FLT is obtained that could be injected to human after a passage through a sterile 0.22 microm filter.     

Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug-free schizophrenics and healthy volunteers

The binding of 11C-labelled clozapine in the brain was studied in three drug-free schizophrenic patients and in three healthy volunteers. High radioactivities were found in the striatum and in the frontal cortex. The rate constantk ₃, which is proportional to receptor association rate and the number of receptors, was lower in the frontal cortex compared to the striatum. No obvious difference between the two brain areas was seen for the dissociation rate constant from the receptors (k ₄). Two schizophrenic patients were reexamined after pretreatment with haloperidol, one after 6 weeks of treatment with a low oral dose, the other one after an IV injection 1 h before 11C-clozapine was given. After haloperidol pretreatment, the binding of 11C-clozapine in striatum and frontal cortex was reduced, more pronounced in the striatum, indicating competition for D-2 dopamine binding sites. Our finding indicates that clozapine has an affinity for a receptor population in the frontal cortex that is predominantly not of the dopamine-D2 type. This feature might be of importance for the unique clinical profile of the drug.     

D1 dopamine receptor binding in mood disorders measured by positron emission tomography

D₁ dopamine receptor binding in mood disorders was studied by positron emission tomography (PET) using¹¹C-SCH23390. Ten patients with bipolar mood disorders and 21 normal controls were studied in the drug-free state. The patients were in euthymic (N=6), depressed (N=3) and manic (N=1) states. Regional radioactivity in the brain was followed for 40 min by PET. A two-compartment model was used to obtain the binding potential (k₃/k₄) for the striatum and frontal cortex. The binding potentials for the frontal cortex for the patients were significantly lower than those for normal controls, whereas those for striatum were not significantly different. These findings suggest that D₁ dopamine receptors in the frontal cortex may be in a different state in patients with bipolar mood disorders.Preliminary results of this study were presented at the 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum, Kyoto International Conference Hall, Kyoto, Japan, September 10–14, 1990     

Evidence for altered hippocampal volume and brain metabolites in workers occupationally exposed to lead: a study by magnetic resonance imaging and (1)H magnetic resonance spectroscopy

Environmental and occupational exposure to lead (Pb) remains to be a major public health issue. The purpose of this cross-sectional study was to use non-invasive magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) techniques to investigate whether chronic exposure to Pb in an occupational setting altered brain structure and function of Pb-exposed workers. The Pb-exposed group consisted of 15 workers recruited from either a Pb-smelting factory or a Pb-battery manufacturer. The control group had 19 healthy volunteers who had no history of Pb exposure in working environment or at home. The average airborne Pb concentrations in fume and dust were 0.43 and 0.44mg/m(3), respectively, in the smeltery, and 0.10 and 1.06mg/m(3), respectively, in the Pb battery workshop. The average blood Pb concentrations (BPb) in Pb-exposed and control workers were 63.5 and 8.7mug/dL, respectively. The MRI examination showed that brain hippocampal volume among Pb-exposed workers was significantly diminished in comparison to age-matched control subjects (p<0.01), although the extent of this reduction was relatively small (5-6% of the control values). Linear regression analyses revealed significant inverse associations between BPb and the decreased hippocampal volume on both sides of brain hemisphere. Among five brain metabolites investigated by MRS, i.e., N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), inosine (mI), glutamate/glutamine (Glx) and lipids (Lip), a significant decrease in NAA/Cr ratio (7% of controls, p<0.05) and a remarkable increase in Lip/Cr ratio (40%, p<0.01) were observed in the brains of Pb-exposed workers as compared to controls. Furthermore, the increased Lip/Cr ratio was significantly associated with BPb (r=0.46, p<0.01). Taken together, this study suggests that occupational exposure to Pb may cause subtle structural and functional alteration in human brains. The MRI and MRS brain imaging techniques can be used as the non-invasive means to evaluate Pb-induced neurotoxicity.     

Radiopharmaceutical chemistry for positron emission tomography

Molecular imaging is an emerging technology that allows the visualization of interactions between molecular probes and biological targets. Molecules that either direct or are subject to homeostatic controls in biological systems could be labeled with the appropriate radioisotopes for the quantitative measurement of selected molecular interactions during normal tissue homeostasis and again after perturbations of the normal state. In particular, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short-lived positron-emitting radionuclide. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the gamma rays formed as a result of the annihilation of the positrons emitted. Despite the great wealth of information that such probes can provide, the potential of PET strongly depends on the availability of suitable PET radiotracers. However, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor for the field of PET. In this review, we provided an overview of the most common chemical approaches for the synthesis of PET-labeled molecules and highlighted the most recent developments and trends. The discussed PET radionuclides include ¹¹C (t_1/2 = 20.4 min), ¹³N (t_1/2 = 9.9 min), ¹⁵O (t_1/2 = 2 min), ⁶⁸Ga (t_1/2 = 68 min), ¹⁸F (t_1/2 = 109.8 min), ⁶⁴Cu (t_1/2 = 12.7 h), and ¹²⁴I (t_1/2 = 4.12 d).     

Effects of age on dopamine D2 receptor availability in striatal subdivisions: A high-resolution positron emission tomography study

The purpose of the present study was to examine the relationship between age and dopamine D₂ receptor availability in striatal subdivisions of young and middle-aged healthy subjects using high-resolution positron emission tomography (PET) with [¹¹C]raclopride to better characterize the nature of age-related decrements in striatal D₂ receptor availability. Twenty-four healthy volunteers completed 3-Tesla magnetic resonance imaging and high-resolution [¹¹C]raclopride PET scans. The analyses using linear and exponential models revealed that age had a significant negative correlation with D₂ receptor availability in the post-commissural putamen (postPU) and that D₂ receptor binding in the postPU decreased significantly more with age than in the ventral striatum, suggesting subregional differences in age-related changes in D₂ receptor binding. The postPU, which belongs to the sensorimotor striatum, may be particularly vulnerable to the effects of age in young and middle-aged subjects.     

Predicting brain concentrations of drug using positron emission tomography and venous input: modeling of arterial-venous concentration differences

Objective In a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T_av).Methods Brain kinetics (C_br) was described as the convolution of arterial plasma kinetics (C_ar) with an arterial-to-brain impulse response function (T_br). The arterial plasma kinetics was obtained as venous plasma kinetics (C_ve) convolved with the inverse of the arterio-venous transform (T_av ⁻¹). The brain kinetics was then given by C_br=C_ve*T_av ⁻¹*T_br. This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.Results The venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.Conclusion We demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.     

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography

Positron emission tomography (PET) and¹¹C-raclopride were used to assess the time course of binding to central dopamine D₂ receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D₂ receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean±2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.     

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and11C-raclopride

Positron emission tomography (PET) and¹¹C-raclopride were used to measure the occupancy of central dopamine D₂ receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of¹¹C-raclopride decreased in a dose dependent manner, and 85% dopamine D₂ receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D₂ receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

超声检查联合核磁共振成像对胎儿颅脑畸形的诊断价值

目的探讨超声检查联合MRI在胎儿颅脑畸形诊断中的应用价值。方法对行超声检查及行MRI检查的12例颅脑畸形的胎儿进行对比分析,并与出生后、引产后及外院检查结果进行比较并评价其准确性。结果12例颅脑畸形的胎儿超声检查明确诊断8例,误诊3例,漏诊1例;MRI明确诊断11例,漏诊1例。结论超声检查是胎儿颅脑畸形筛查的必选检查,MRI检查可以作为超声检查补充诊断方法,两者联合在指导孕妇确定是否继续妊娠方面具有重要的指导意义。     

磁共振扩散加权成像在诊断前列腺良恶性病变中的应用

目的 探讨磁共振扩散加权成像( DWI)对前列腺良、恶性病变的诊断价值.方法 选取前列腺良、恶性病变患者90例,其中良性病变56例,恶性病变34例.90例患者均进行磁共振DWI扫描,分析前列腺良、恶性病变的DWI表现和扩散系数(ADC)图表现,并进行比较.结果 前列腺癌病灶在DWI上呈高信号,ADC图呈低信号;前列腺增生的DWI和ADC图表现为中央腺体区信号不均匀,而外周带信号均匀;前列腺增生组和前列腺癌组的平均ADC值比较差异有统计学意义(P＜0.05).结论 磁共振DWI检查在前列腺良、恶性病变诊断中有重要的临床价值,并对前列腺增生和前列腺癌具有鉴别诊断价值.