A method is described for the labelling of the antidepressant clomipramine with11C. A product of 10–20 mCi is obtained in 40 min after the irradiation. The chemical and radiochemical purity of11C-clomipramine is investigated.

The authors of the present paper reported the synthesis of [C-11]-ohmefentanyl in a symposium abstract in 1991(1). We here describe the results of synthesis and analysis in detail. Ohmefentanyl 1 is a novel, highly potent and selective agonist for opiate mu-receptors. In order to visualize the mu-receptor by Positron Emission Tomography (PET), this compound was labelled with carbon-11. The unlabelled cis-A-ohmefentanyl was prepared in a nine-step synthesis and two-step fractional crystallization, and the OH-precursor 11 for [C-11]-ohmefentanyl labelling was obtained by hydrolysis of the 4-N-propionyl group of cis-A-ohmefentanyl in 6 N hydrochloric acid. The [C-11]-propionyl chloride was prepared by carbonation of ethylmagnesium bromide with cyclotron-produced [C-11]-carbon dioxide followed by direct treatment of the intermediate complex with phthaloyl dichloride and 2,6-di-t-butylpyridine. Reaction of the OH-precursor 11 with [C-11]-propionyl chloride yields [C-11]-ohmefentanyl separated by HPLC, with a high specific activity of 11.1 - 14.8 GBq mumol-1 (300-400 mCi mumol-1), 49 minutes after the end of bombardment.The keto-precursor 12, prepared by hydrolysis of the 4-N-propionyl group of cis-10 in 8 N hydrochloric acid, was also used for [C-11]-ohmefentanyl labelling. Reaction of the [C-11]-propionyl chloride with keto-precursor 12, followed by addition of sodium borohydride, yields [C-11]-ohmefentanyl.The [C-11]-labelled ohmefentanyl obtained using the OH-precursor 11 is a cis-A form, while that obtained using the keto-precursor is a mixture of cis-A and cis-B forms.

LY186126 [1,3-dihydro- 1,3,3-trimethyl-5-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-indol-2-one], an analogue of the cardiotonic agent indolidan, is a potent, selective and competitive inhibitor of an isozymic form of cyclic AMP phosphodiesterase. LY186126 was labelled with carbon-11 to permit pharmacological studies in the dog myocardium by positron emission tomography.Alkylation with [C-11]methyl iodide of N-norLY186126 (LY-197055) allowed the production of 1.7 GBq (50 mCi) of [C-11]LY-186126 in 40 min. The product, after purification by HPLC, was obtained with a specific radioactivity ranging from 22.2 to 33.3 GBq.mu-mol-1 (600-900 mCi.mu-mol-1).

A double-blind study was carried out to assess the efficiency and possible side-effects of a single epidural injection of either morphine or buprenorphine at equipotent doses after elective thoracic surgery. The series included 24 patients aged 53.7 +/- 11.4 years; 13 underwent a lobectomy and 11 a pneumonectomy. 6 h after the last intravenous injection of fentanyl, the patients were randomly allocated to one of three equal groups. They received an epidural injection at T8-9 or T9-10 level of either 100 micrograms.kg-1 morphine (group M) or 6.6 micrograms.kg-1 buprenorphine (group B) or a subcutaneous injection of 0.1 ml.kg-1 normal saline placebo at the same level (group T). The following parameters were measured 20 and 60 min, and every 6 h up to 48 h after the injection: patient wakefulness, respiratory rate, blood gases, pain (according to a verbal scale), FVC and FEV1, adverse effects (euphoria, hallucinations, sweating, facial pruritus, nausea) and atelectasis. The duration of surgery, the anaesthetic protocol, the age, weight and height, as well as all the parameters before injection were similar in all three groups. There was a fall in pain intensity from the 20th min to the 24th hour in group M and from the 20th min to the 36th hour in group B, significant for both groups when compared with group T. Similarly, there was a prolonged increase in FEV1 in both groups M and B. There was no case of severe respiratory depression; PaCO2 was increased at the 1st hour (+0.3 +/- 0.6 kPa) in group B and at the 6th hour (+0.5 +/- 0.7 kPa) in group M.(ABSTRACT TRUNCATED AT 250 WORDS)

Les avantages et les risques d'une injection péridurale unique d'une dose équipotente de buprénorphine (6,6 μg · kg−1) ou de morphine (100 μg · kg−1) après chirurgie thoracique ont été évalués. Huit patients ont reçu de la buprénorphine, huit de la morphine, huit une injection de placebo. Les trois groupes étaient comparables en ce qui concerne la durée des interventions, la technique anesthésique, l'âge, le poids, la taille, les paramètres fonctionnels respiratoires préopératoires des patients, ainsi que les valeurs des paramètres d'évaluation avant l'injection. Par rapport au groupe témoin, une diminution significative d'intensité douloureuse a été observée de la 20e min à la 24e h avec la morphine et de la 20e min à la 36e h avec la buprénorphine. Une amélioration significative et durable du volume expiratoire maximum par seconde a été observée avec la morphine et la buprénorphine. Il n'a pas été observé de dépression respiratoire grave ; une élévation de la pression artérielle en gaz carbonique a été relevée à la lre h avec la buprénorphine et à la 6e h avec la morphine. Une augmentation modérée mais significative du degré de sédation a été notée avec les deux produits. 75 % des patients témoins ont dû subir une bronchoscopie en raison d'un encombrement important ou d'atélectasies, contre 18,7 % seulement dans les groupes traités. Les résultats observés montrent qu'une injection péridurale postopératoire unique de morphine ou de buprénorphine aux doses utilisées permet d'obtenir une analgésie satisfaisante après chirurgie thoracique, au prix d'effets secondaires minimes. Dans cette indication, la buprénorphine semble offrir l'avantage d'une analgésie prolongée.

As positron emission tomography is becoming a very important tool to obtain metabolic images, we thought it useful to give recent EEC workshop reports on this subject greater circulation.

Bromolisuride, an ergoline derivative, was labeled with the positron emitter radionuclide, bromine 76. In vitro and in vivo binding and competition studies in rats demonstrated a high affinity (KD = 0.3 nM) and a high specificity of this new radioligand for D-2 dopamine receptors. PET kinetic studies in baboons showed an accumulation of [76Br]bromolisuride in the striatum which reached a maximum 30 min post-injection and which could be displaced by haloperidol. All these results indicated that this new ligand is certainly suitable for the non-invasive in vivo quantitative imaging of D-2 dopamine receptor sites in humain brain.

A highly efficient and rapid technique for labelling serum albumin microspheres with 68Ga is described. Measurements of the in vivo stability of the radiopharmaceutical in the rabbit and the baboon show that less than 0.2% of the injected activity is eluted from the microspheres in 2 h.

To investigate further the topographical, clinical and temporal correlates of crossed cerebellar diaschisis (CCD) after supratentorial stroke, 55 patients suffering from a single unilateral ischaemic stroke in the carotid artery territory were studied with the quantitative oxygen-15 steady-state technique and positron tomography. Fourteen patients had one or more follow-up studies, contributing a total of 72 studies. The phenomenon of CCD, defined by depressed oxygen consumption in the contralateral cerebellum, was statistically significant in 58% of the studies. It was more prominent when the supratentorial infarct involved the internal capsule or the cortical mantle extensively, consistent with the hypothesis that it results from destruction of the corticopontocerebellar fibres. Although CCD was associated with the presence of hemiparesis, it also occurred in patients without hemiparesis and was not seen in all those with hemiparesis, suggesting that destruction of the pyramidal tract is neither necessary nor sufficient to induce CCD. Finally, CCD tended to persist over long periods of time after a stroke, pointing towards a transneuronal degeneration possibly akin to crossed cerebellar atrophy as a likely explanation for CCD. Nevertheless, CCD could be seen within hours of a stroke and sometimes disappeared within a few days, suggesting a temporal continuum between early, potentially reversible functional hypometabolism (diaschisis) and irreversible degeneration.

Fluorination of aromatic rings with no carrier added (n.c.a.) 18F-fluoride was investigated using aryl triazenes and aryl iodides as substrates. Aryl triazenes give low yields of labeled under all conditions, and evidence was obtained to indicate that an inert solvent was unnecessary for the reaction. Nucleophilic substitution of aromatic iodides in DMSO was found to be a superior method of fluorination yielding up to 70% incorporation of label. The scope and limitations of this new labeling reaction are reported.

Electrical stimulation of the olfactory bulb (OB) produces an evoked potential in the pyriform cortex (PC) characterized by an initial surface-negative wave (period 1) representing activation of PC pyramidal cells via the lateral olfactory tract, followed by a surface-positive wave (period 2) which is temporally associated with recurrent and feed-forward inhibition. The experiment reported here examined the changes that occur in the PC evoked potential following a pattern of stimulation that has been found to produce short- and long-term potentiation (LTP) in other areas of the forebrain. Male Long-Evans rats with electrodes in the OB and PC were divided into two groups. LTP animals received high-frequency stimulation of the OB (30 trains of 10 pulses each at a frequency of 100 Hz). Control animals received the same number of pulses at a lower frequency (1 Hz). This procedure was repeated 6 times at 2-day intervals. Neither high- nor low-frequency stimulation altered period 1 of the PC evoked potential, indicating that synaptic input arriving via the lateral olfactory tract was unaffected. However, LTP animals exhibited a marked increase in the amplitude and duration of period 2 which appeared to reflect two separate processes: a short-term change that peaked within 30 min of the trains; and a long-term change that accumulated across the 6 treatments. LTP of period 2 persisted in latent form for at least 32 days after the last treatment. Control animals exhibited only small changes that were attributed to the paired-pulse stimulation used for testing rather than the 1 Hz Control trains. These results suggest that repeated high-frequency stimulation of the OB causes a persistent alteration in the way information is processed within the PC. The form of LTP demonstrated here is markedly different from that found in the hippocampal formation, where potentiation of the monosynaptic excitatory postsynaptic potential is a prominent effect. The functional significance of this change cannot be determined with certainly from the present experiment, but available evidence suggests that it represents an enhancement of inhibitory processes within the PC.

The brain regional distribution and kinetics of RO 15-1788, a benzodiazepine (BZD) antagonist labeled with 11C was studied by time-of-flight positron tomography after intravenous injection in four normal human volunteers. In two control studies, there was a high uptake of [11C]RO 15-1788 in gray matter structures initially (brain/blood ratio ∼ 3), and subsequent retention that was highest in cerebral cortex, a structure known to have a high density of BZD receptors in vitro. Variation in tissue kinetics of [11C]RO among different gray matter structures may, however, suggest regional differences in binding characteristics or environment of BZD receptors. In two displacement studies, unlabeled RO 15-1788 was injected ten minutes after the radioligand: there was an immediate and marked washout of [11C]brain radioactivity that reached 70% in the occipital cortex with a 0.05 mg/kg dose (indicating a high specific to non-specific binding ratio) but was less prominent with a 0.01 mg/kg dose. These data suggest that [11C]RO 15-1788 may be useful for in vivo mapping of human brain BZD receptors using positron tomography.

The muscarinic receptor was studied in vivo in the human heart by a noninvasive method, positron emission tomography (PET). The study showed that the binding sites of 11C-labeled methiodide quinuclidinyl benzilate [( 11C]-MQNB), a muscarinic antagonist, were mainly distributed in the ventricular septum (98 pmol/cm3 of heart) and in the left ventricular wall (89 pmol/cm3), while the atria were not visualized. A few minutes after a bolus intravenous injection, the concentration of [11C]MQNB in blood fell to a negligible level (less than 100th of the concentration measured in the ventricular septum). When injected at high specific radioactivity, the concentration of [11C]MQNB in the septum rapidly increased and then remained constant with time. This result was explained by rebinding of the ligand to receptors. It was the major difference observed between the kinetics of binding of [11C]MQNB to receptor sites after intravenous injection in vivo and that of [3H]MQNB to heart homogenates in vitro. The MQNB concentrations in the ventricular septum of different individuals were found to be highest when the heart rate at the time of injection was slow. This result suggests that the antagonist binding site is related to a low-affinity conformational state of the receptor under predominant vagal stimulation. Thus, positron emission tomography might be the ideal method to study the physiologically active form of the muscarinic acetylcholine receptor in man.