Initial evaluation of123|-5-|-R91150, a selective 5-HT2A ligand for single-photon emission tomography, in healthy human subjects

The mapping of 5-HT₂ receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (¹²³I-5-I-R91150 or¹²³I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT_2A receptors. This study reports on preliminary¹²³I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT_2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT_2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that¹²³I-5-I-R91150 may be used for the imaging of 5-HT_2A receptors in the living human brain with SPET.     

PET in cardiology: current status and clinical expectations

Summary. The development of positron emission tomography (PET) in the clinical environment along with the synthesis of biologically active molecules and tracer kinetic principles has provided a diagnostic tool for in vivo tissue characterization in humans. Moreover, based on the growing knowledge of cellular function on the molecular level of diseases PET biological imaging has stimulated the synthesis of numerous metabolic compounds labelled with the four primary positron-emitting radioisotopes C-ll, F-18, N-13 and 0–15. While the concept of biological imaging has gained attraction for probing both the central nervous system and neoplastic tissues, current diagnostic benefit from PET is probably best defined in cardiovascular medicine.     

Fast acquisition of myocardial SPECT images with Tc-99m sestamibi for the diagnosis of coronary artery disease

Background  Shortening the acquisition time for myocardial single-photon emission computed tomographic (SPECT) imaging increases patient comfort and laboratory throughput. The purpose of this study was to compare the diagnostic accuracy for coronary artery disease detection of myocardial SPECT images acquired in 5 to 10 minutes versus 25 minutes using Tc-99m methoxyisobutylisonitrile (Tc-99m sestamibi) and a single-head gamma camera. Methods and Results  Forty-one subjects had a standard 1-day rest/stress Tc-99m sestamibi myocardial SPECT study. Two sets of rest and stress images were acquired on the same day for each subject. One set of images was acquired with a 5- to 10-minute fast acquisition protocol; the second set of images was acquired with a 25-minute standard protocol. The accuracies of the fast and standard protocols for identifying individuals with and without coronary artery disease were equivalent. Accuracy was 76% for the fast protocol and 73% for the standard protocol in individuals with at least one coronary stenosis ≥70%. The accuracies of the two protocols for identifying individual coronary arteries with stenoses ≥70% also were equivalent. Accuracy was 77% for the fast protocol and 74% for the standard protocol. Conclusions  SPECT myocardial images may be acquired in as little as 5 to 10 minutes using Tc-99m sestamibi and a 1-day rest/stress protocol. Accuracy is equivalent to that attained in studies with longer imaging time.     

Lack of effect of a single dose of hydrocortisone on serotonin(1A) receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635.

BACKGROUND: Elevated cortisol levels might account for the reduction in central serotonin 1A (5-hydroxytryptamine [5-HT](1A)) receptor binding and function observed in patients with major depression. We tested this hypothesis by studying the effect of acute administration of hydrocortisone on 5-HT(1A) receptor binding potential (BP) in subjects recovered from depression. METHODS: We studied 14 subjects (8 male, 6 female) who had recovered from at least two episodes of major depression and had been euthymic and drug free for at least 6 months. Serotonin 1A receptor BP was measured by [(11)C]WAY-100635 in conjunction with positron emission tomography. Subjects were tested on two occasions in a double-blind, random-order, crossover design after administration of either hydrocortisone (100 mg orally) or placebo 12 hours previously. Positron emission tomography scans were analyzed with a region of interest analysis. RESULTS: Hydrocortisone treatment did not decrease 5-HT(1A) receptor BP either in the hippocampus, which was our a priori hypothesis, or in other cortical 5-HT(1A) regions; however, female subjects had a higher 5-HT(1A) receptor BP in certain brain areas compared with male subjects. CONCLUSIONS: These data are consistent with an earlier study in healthy volunteers and do not support the proposal that decreased 5-HT(1A) receptor BP in patients with acute major depression is a consequence of cortisol hypersecretion.     

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.     

马蹄莲不同部位微量元素的含量测定

目的 探讨马蹄莲不同部位微量元素的含量。方法 用发射光谱法、原子吸收法测定了马蹄莲根、茎、叶中20种微量元素的含量。结果 马蹄莲根、茎、叶中含有12种人体必需微量元素，其中Fe、Mn、Zn、Si、Li、Ca等七种元素含量较高。结论 马蹄莲富含多种人体必需的微量元素，预示马蹄莲具很高的药理保健价值。     

An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [¹⁸F]-setoperone for 5-HT2 binding potential (BP) and [¹¹C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [¹⁸F]-setoperone and with [¹¹C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as ≥50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.     

Detection of moderate and severe coronary artery stenosis with technetium-99m tetrofosmin myocardial single-photon emission tomography

The aim of this study was to determine the diagnostic accuracy of technetium-99m tetrofosmin myocardial imaging for the localization of coronary artery stenoses of different degrees of severity. Stress-rest single-photon emission tomography (SPET) was performed on separate days in 80 patients (64 males, 16 females; mean age 61 years; 43 patients with previous myocardial infarction; 18 patients with pharmacological stress), within 6 months of coronary angiography. Scintigraphic images were blindly and independently evaluated by three observers. Coronary stenosis was defined as a >50% narrowing in luminal diameter; severe stenosis was defined as a proximal stenosis of >75% or a peripheral stenosis of >90%. Coronary angiography revealed normal coronary arteries or insignificant coronary stenosis in 13 patients and significant coronary stenoses in 67 patients. The sensitivity and specificity of ^99mTc-tetrofosmin SPET in respect of severely stenosed vessels were, respectively, 80% and 65% for the left anterior descending artery (LAD), 100% and 46% for the right coronary artery (RCA) and 58 and 78% for the left circumflex artery (LCx) territories. Considering all the significantly stenosed vessels, a significant decrease in sensitivity was observed for LAD territories (to 59%, P=0.05), and a nonsignificant decrease for RCA (88%) and LCx (47%) territories while specificity values remained essentially unchanged. No significant changes in sensitivity or specificity were observed when regions with previous myocardial infarction were excluded. In conclusion, the sensitivity of ^99mTc-tetrofosmin SPET for the localization of individual stenosed vessels is only moderate when all significant stenoses are considered, but the ability of this technique to predict the location of severe coronary artery stenoses seems satisfactory, with the exception of the low specificity in respect of RCA territories. Received 26 April and in revised form 7 June 1997     

Positron emission tomographic investigations of central muscarinic cholinergic receptors with three isomers of [76Br]BrQNP

We studied the potential of three radiobrominated isomers of BrQNP, (Z(-,-)-[⁷⁶Br]BrQNP,E(-,-)-[⁷⁶Br]BrQNP andE(-,+)-[⁷⁶Br]BrQNP), as suitable radioligands for imaging of central muscarinic cholinergic receptors in the human brain. These radioligands were stereospecifically prepared by electrophilic radiobromodestannylation of the respective tributylstannyl precursors using no-carrier-added [⁷⁶Br]BrNH₄ and peracetic acid. Preliminary pharmacological characterizations were determined by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented important specific uptakes in brain muscarinic cholinergic receptor (mAChR)-rich structures and in heart, low metabolization rates and an apparent M₂ selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M₁ selectivity. Reversibility of the binding was confirmed for the three radiotracers. Positron emission tomography in the living baboon brain revealed high and rapid uptake in the brain and accumulation in the mAChR-rich structures studied. At 30 min p.i., theE(-,-)-radiotracer reached a plateau in cortex, pons and thalamus with concentrations of 29%, 24% and 19% ID/l, respectively.Z(-,-)-[⁷⁶Br]BrQNP also accumulated in these structures, reaching a maximal uptake (27% ID/l) in the cortex 2 h p.i. At 5 min p.i. a plateau (17% ID/l) was only observed in the cortex for theE(-,+)-[⁷⁶Br]BrQNP; by contrast, the other structures showed slow washout. After 3 weeks, the (-,-)-radiotracers were studied in the same baboon pretreated with dexetimide (1 mg/kg), a well-known muscarinic antagonist. In all the mAChR structures, the highly reduced uptake observed after this preloading step indicates that these radiotracers specifically bind to muscarinic receptors.Z(-,-)-[⁷⁶Br]BrQNP, which is displaced in higher amounts from M₂ mAChR-enriched structures, reveals an M₂ affinity. The two isomers having the (-,-)-configuration are potential probes for investigating central muscarinic receptors. The absolute configuration on the acetate chiral centre influences their muscarinic subtype selectivity and thecis-trans isomerism of the vinyl moiety affects their specific fixation.     

Improvement of oxygen metabolic reserve after extracranial-intracranial bypass surgery in patients with severe haemodynamic insufficiency

Summary The effectiveness of extracranial-intracranial arterial bypass (EC-IC bypass) surgery on impaired haemodynamic status was studied in 12 patients with reduced regional cerebral perfusion pressure (rCPP) and elevated regional oxygen extraction fraction (rOEF) in the area distal to the symptomatic arterial lesion. Postoperative positron emission tomography (PET) study demonstrated a statistically significant decrease of rOEF in the operated hemispheres with disappearance of the pre-operative interhemispheric rOEF difference. Regional cerebral blood flow (rCBF) and regional cerebral oxygen metabolism (rCMRO2) were also increased in the operated hemispheres with disappearance of the pre-operative interhemispheric differences. Regional CBF/regional cerebral blood volume (rCBV) ratios of the symptomatic hemispheres were increased after surgery, but were still lower than in the contralateral hemispheres. We conclude that EC-IC bypass surgery improves impaired cerebral oxygen metabolic reserve.