The effect of the muscarinic antagonist scopolamine on regional cerebral blood flow during the performance of a memory task

Scopolamine, a muscarinic antagonist, impairs memory performance in both humans and animals. In this study, repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers whilst performing auditory verbal memory tasks, before and after the administration of scopolamine (0.4 mg s.c.) or placebo. Compared to placebo, scopolamine increased blood flow in the lateral occipital cortex bilaterally and the left orbitofrontal region. Scopolamine decreased rCBF in the region of the right thalamus, the precuneus and the right and left lateral premotor areas. Scopolamine attenuated memory-task-induced increases of rCBF in the left and right prefrontal cortex and the right anterior cingulate region. These data suggest that acute blockade of cholinergic neurotransmission affects diverse brain areas, including components of the visual and motor systems, and, in addition, modulates memory task activations at distinct points in a distributed network for memory function.     

The Bücherer-Strecker synthesis of d- and l-(1-11C)tyrosine and the in vivo study of l-(1-11C)tyrosine in human brain using positron emission tomography

The synthesis of d-and l-(1-¹¹C)tyrosine, starting with ¹¹C-cyanide, is reported. dl-(1-¹¹C)Tyrosine was prepared by the Bücherer-Strecker reaction, from carrier added ¹¹C-cyanide with an incorporation of 80% in 20 min. The isolation of the pure d- and l-amino acid isomers from the enantiomeric mixture was accomplished within 15 min by preparative HPLC using a chiral stationary phase and a phosphate buffer as the mobile phase. Typically, the total synthesis time was 50 min (including purification) from end of trapping of ¹¹C-cyanide, with a radiochemical yield of d- and l-amino acid of 40%–60%. The d- and l-(1-¹¹C)tyrosine were both obtained optically pure, with a carrier added specific activity of 0.3–0.5 Ci/mmol and a radiochemical purity better than 99%. The ¹¹C labelled l-tyrosine was used in an in vivo study in the human brain using positron emission tomography (PET).     

Remote metabolic effects of cerebrovascular lesions: magnetic resonance and positron tomography imaging

Summary Combined Positron Emission Tomography (PET) and Proton Magnetic Resonance Imaging (MRI) study were performed in six patients with chronic supratentorial stroke to investigate whether remote hypometabolic regions revealed by PET showed any abnormality on MRI. Either regional oxygen consumption (n=4) or glucose utilization (n=2) were measured using PET and the ¹⁵O steady state ¹⁸FGD technique, respectively. Four patients, with deeply located brain lesions, showed a significant metabolic reduction in the overlying cerebral cortex. In the remaining two patients, affected by a large cortical infarct, there was a significant crossed cerebellar hypometabolism. The MRI weighted by the parameters spin density (), spin lattice (T₁) and spin-spin (T₂) relaxation times were obtained employing various sequences in the same subjects. In no patient did the MRI show any contrast modification in these hypometabolic remote regions, suggesting that subtle loss of tissue and/or biochemical change do not underlie the reduction in metabolic rate.     

Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET)

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-¹¹C)-tyrosine by ¹¹C-carboxylation of the appropriate -lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-¹¹C)-Tyrosine in 0.1 N NaH₂PO₄ buffer was prepared with a radiochemical yield of 8%–16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-¹¹C)-tyrosine in physiological saline was obtained in 2%–4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-¹¹C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.     

The continuing important role of radionuclide generator systems for nuclear medicine

In this review, the continuing importance and status of development of radionuclide generator systems for nuclear medicine are discussed. Radioisotope costs and availability are two important factors, and both nuclear reactors and accelerator facilities are required for production of the parent radioisotopes. Radionuclide generator research is currently focused on the development of generators which provide radioisotopes for positron emission tomography (PET) applications and daughter radioisotopes for various therapeutic applications which decay primarily by particle emission. Generator research continues to be influenced by developments and requirements of complementary technologies, such as the increasing availability of PET. In addition, the availability of a wide spectrum of tumor-specific antibodies, fragments, and peptides for radio-immunodiagnosis and radioimmunotherapy has stimulated the need for generator-derived radioisotopes. The advantages of treatment of arthritis of the synovial joints with radioactive particles (radiation synovectomy) may be expected to be of increasing importance as the elderly population increases, and many of these agents are prepared using generator-derived radioisotopes such as yttrium-90 and rhenium-188. Therapeutic use of the in vivo generator is a new approach, where the less radio-toxic parent radioisotope is used to prepare tissue-speciic therapeutic agents. Following in vivo site localization, decay of the parent provides the daughter for therapy at the target site. The principal foundation of most diagnostic agents will continue to require technetium-99m from the molybdenum-99/technetium-99m (Moly) generator. With the limited availability of nuclear reactors and facilities necessary for production and processing of fission ^99mTc and the significant issues and problems associated with radioactive waste processing, however, the possibility of utilizing lower specific activity ⁹⁹Mo produced from neutron activation of enriched ⁹⁸Mo may become practical in the future. Correspondence to: RE Knapp, Jr.     

In vivo labeling of sigma receptors in mouse brain with [3H]4-phenyl-1-(4-phenylbutyl)piperidine

4-Phenyl-1-(4-phenylbutyl)piperidine(4-PPBP) is a very potent ligand for σ (Sigma) receptors. The present study was undertaken to evaluate [³H]4-PPBPas a radioligand for in vivo labeling of cerebral σ receptors. After intravenous administration of [³H]4-PPBP to mice, there is high uptake of radioactivity in the brain. The regional distribution of radioactivity in the brain 2 h after intravenous injection of [³H]4-PPBP parallels the in vitro binding of the radioligand in rat brain (pons/medulla > cerebellum ≥ prefrontal cortex ≥ parietal cortex > hypothalamus > olfactory tubercle ≥ thalamus > hippocampus > striatum). Pretreatment with haloperidol (2 mg/kg) significantly decreases the radioactivity measured in the brain 30–120 min after injection of [³H]4-PPBP. Pretreatment with unlabeled 4-PPBP or ifenprodil also significantly decreases radioactivity in the brain 2 h after injection of [³H]4-PPBP, in a dosedependent manner. The in vivo binding of [³H]4-PPBP in the brain also is significantly inhibited by SL 82.0715, BMY 14802, 1,3-di-o-tolylguanidine (DTG), and (+)-enantiomers of pentazocine, SKF 10,047, and 3-PPP, but not by the corresponding (?)-enantiomers, consistent with stereoselectivity of inhibition obtained in in vitro binding studies. In contrast, pretreatment with dizocilpine and spiperone does not inhibit in vivo binding of [³H]4-PPBP. The results indicate that [³H]4-PPBP would be a suitable radioligand for in vivo labeling of σ receptors in brain. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America

.     

Identification of the central vestibular projections in man: a positron emission tomography activation study

The cerebral representation of space depends on the integration of many different sensory inputs. The vestibular system provides one such input and its dysfunction can cause profound spatial disorientation. Using positron emission tomography (PET), we measured regional cerebral perfusion with various vestibular stimulations to map central vestibular projections and to investigate the cerebral basis of spatial disorientation. We showed that the temporoparietal cortex, the insula, the putamen, and the anterior cingulate cortex are the cerebral projections of the vestibular system in man and that the spatial disorientation caused by unilateral vestibular stimulation is associated with their asymmetric activation.     

Non-invasive assessment of skeletal kinetics using fluorine-18 fluoride positron emission tomography: evaluation of image and population-derived arterial input functions

To measure regional skeletal kinetics using fluorine-18 fluoride positron emission tomography (PET) it is necessary to know the concentration of radioactive tracer being delivered to bone by arterial plasma with relation to time, the arterial input function (IFa). Methods by which IFa can be derived without arterial sampling are attractive because of their relative technical simplicity and the reduction in possible morbidity to the subject. We have compared the use of a scaled population input function (IFp) and a corrected image-derived input function from the aorta (IFi) with an IFa directly measured from a radial artery line in ten normal postmenopausal women. Both of the aforementioned methods rely only on a small number of discrete venous samples. Each subject had a dynamic PET acquisition of the lumbar spine performed after the intravenous injection of 180 MBq ¹⁸F-fluoride. Both the IFp and the IFi were compared with the IFa in terms of the accuracy of determination of six parameters. These were: plasma clearance of fluoride to bone mineral (K _i), unidirectional plasma clearance to total bone tissue (K ₁) and individual rate constants k ₂, k ₃ and k ₄, calculated using non-linear regression with a three-compartment model, and the plasma clearance to bone mineral calculated using the Patlak method (K _pat). For both the IFp and the IFi method the root mean square errors for K _pat and K _i were similar and small (<8.2%). The errors in determining K ₁ and the rate constants k ₂ to k ₄ are larger by either method, but with a small advantage using the IFp method. It is concluded that the use of either non-invasive method for determining the arterial plasma input function is suitable for the measurement of the most important parameters, K _i and K _pat, in these subjects. Received 8 April and in revised form 11 July 1999     

Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography

The augmentation effect of (–)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-¹¹C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT_1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT_1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT_1A receptor occupancy was within the range 7–21% in the three subjects. The study confirms that the 5-HT_1A-receptor may be a clinically significant target for pindolol. Received: 8 March 1999 / Final version: 15 March 1999     

The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer: a comparative study with X-ray computed tomography

We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer and then compared the findings with the results of X-ray CT by region based on the histological diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred and thirty-two mediastinal lymph nodes were surgically removed and the histological diagnoses were confirmed. FDG PET images, including 146 mediastinal regions, were visually analysed and the mediastinal lymph nodes were scored as positive when the FDG uptake was higher than that in the other mediastinal structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of 10 mm or larger were scored as positive. All three examinations were successfully performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A significant difference was observed in respect of both specificity and accuracy (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X-ray CT when used for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer.