Johan Ulin

Decreased uptake and binding of11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography

SummaryPositron emission tomography of the brain following intravenous injection of (+) (R) and (−) (S) N-[11C-methyl]nicotine showed a marked reduced uptake of both isomers, especially the (R) form, in Alzheimer patients as compared to age-matched controls. The significantly larger difference between the uptake values of the (S)- and (R)-enantiomers of11C-nicotine in Azheimer brains may be of diagnostic value.

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson's disease measured with positron emission tomography

The kinetics in brain of the dopamine reuptake blocking agent [11C]‐(+)‐nomifensine and the L‐dopa analogue 6‐[18F]fluoro‐L‐dopa were compared in 3 patients with idiopathic Parkinsons disease and age‐matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3‐compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinsons disease. A fairly constant ratio between 6‐[18F]fluoro‐L‐dopa utilization and [11C]‐(+)‐nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinsons disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.

Uptake and regional distribution of (+)-(R)- and (−)-(S)-N-[methyl-11C]-nicotine in the brains of Rhesus monkey an attempt to study nicotinic receptors in vivo

SummaryN-[methyl-11C] nicotine (11C-nicotine) was given intravenously to monkeys and the uptake and regional distribution of radioactivity was followed in the brain using positron emission tomography (PET). The11C-radioactivity in the brain peaked within 1–2 min and then rapidly declined. Pretreatment with unlabelled nicotine (10 μg/kg) reduced the uptake of11C-radioactivity to the brain by 30%. The uptake of radioactivity was higher following (+)11C-nicotine than (−)11C-nicotine. Both enantiomers were distributed in a similar manner within the brain. When animals were infused with a peripheral nicotinic blocker (trimetaphan) the uptake of radioactivity to the brain was lower following (+)11C-nicotine compared to (−)11C-nicotine. The amount of radioactivity was high in the occipital cortex, thalamus, intermediate in the frontal cortex and low in white matter in (−)11C injected monkeys while no regional difference in distribution of11C-radioactivity was observed after injection of (+)11C-nicotine.

Striatal binding of 11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia: no evidence for altered dopamine D2 receptor binding

Dopamine D2 receptor binding characteristics were studied by positron emission tomography (PET) using N-11C-methyl spiperone as receptor ligand in patients on longterm treatment with neuroleptic drugs and in control subjects. Eight of the patients had symptoms of tardive dyskinesia whereas three patients did not have any symptoms. Control subjects comprised 5 healthy volunteers and 7 patients with pituitary tumors. All patients had been free of neuroleptic drugs for at least 4 weeks. The time dependent regional radioactivity in the striatum was measured and the receptor binding rate, k3, proportional to receptor number, Bmax and association rate for the receptor was calculated in relation to the cerebellum. The lack in difference in k3 values between TD patients, neuroleptic treated patients without TD and control subjects throws doubt on the hypothesis that changes in striatal D2 dopamin receptor number or binding affinity is an etiological mechanism for persistent TD.

Synthesis of racemic (+) and (−) N-[methyl-11C]nomifensine, a ligand for evaluation of monoamine re-uptake sites by use of positron emission tomography

The synthesis of racemic or enantiomeric N-[methyl-11C]nomifensine (1,2,3,4-tetrahydro-2-[11C]methyl-4-phenyl-8-isoquinolinamine), a potential ligand for the evaluation of monoamine re-uptake sites at the presynaptic dopaminergic terminals, using the appropriate N-desmethylcompounds and [11C]methyl iodide is described. The radiochemical conversion of [11C]methyl iodide to [11C]nomifensine was in the order of 85-95%. Radiochemical purity of the LC-purified radiopharmaceutical was in the order of 98-99%. In a typical run, starting with 120 mCi (4.4 GBq) of [11C]carbon dioxide, 380 MBq (8.6% not decay corrected) of a final solution was obtained within 55 min (roughly 20 min of that is related to transport time). The specific radioactivity corresponding to the [11C]methyl iodide was 30-100 mCi/mumol (typical: a total mass of 30 micrograms and 150 MBq was administered in the PET-studies). A procedure for resolving the racemate of N-desmethylnomifensine (1,2,3,4-tetrahydro-4-phenyl-8-isoquinoline) into its enantiomers using triacetylcellulose as the stationary phase and methanol/ethanol as solvents by use of LC is also described.

Synthesis of the 11C-labelled β-adrenergic receptor ligands atenolol, metoprolol and propranolol

Abstract The 11C-labelled β-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using [2-11C]isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from [11C]carbon dioxide and obtained in 40% radiochemical yield within 14 min reaction time. The total reaction times for compounds 1–3, counted from the start of the isopropyl iodide synthesis and including purification were 45–55 min. The products were obtained in 5–15% radiochemical yields and with radiochemical purities higher than 98%. The specific activity ranged from 0.4 to 4 GBq/μmol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained.

Ventilation Distribution Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label

Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using 68Ga-labeled pseudogas or “Gallgas” with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.

Regional distribution of 11C-labeled lidocaine, bupivacaine, and ropivacaine in the heart, lungs, and skeletal muscle of pigs studied with positron emission tomography

The regional myocardial uptake and kinetics of 11C-lidocaine, 11C-bupivacaine, and 11C-ropivacaine were examined in the pig, utilizing positron emission tomography to determine whether disproportionate distribution exists among these agents. The three drugs were rapidly distributed to the myocardium and lung with mean peak radioactivities occurring between 0.35 and 0.48 min post-injection in myocardium and 0.35 and 0.65 min in lung. Radioactivities peaked later in skeletal muscle than in the myocardium and lung, occurring between 1.1 and 2.7 min post-end injection. Blood radioactivities for bupivacaine and ropivacaine were significantly higher than those of lidocaine, whereas myocardial, lung, and muscle uptakes for the three agents were not significantly different. Myocardium-blood partition coefficients were similar for bupivacaine and ropivacaine (0.55 and 0.49 respectively), while it was three times higher for lidocaine (1.4). A similar relationship existed for skeletal muscle- and lung-blood partition coefficients. Bupivacaine and ropivacaine t1/2z in skeletal muscle were significantly longer than those of lidocaine. The results of this study indicate that the increased cardiotoxicity associated with bupivacaine does not appear to be related to disproportionate distribution in the myocardium when compared to lidocaine and ropivacaine.

Maternal Blood Volume in Placenta of the Rhesus Monkey Measured in vivo by Positron Emission Tomography

The relative volume of the intervillous space of the placenta of the rhesus monkey was measured in vivo using positron emission tomography (PET), a noninvasive tracer technique. 11CO-Hb and 68GaCl3 were both used in three experiments and 68Ga-EDTA in two. The tracers were administered intravenously as bolus doses to 6 pregnant monkeys during 7 different pregnancies. Measurements with 11CO-Hb gave a volume of 48.0% of the total placental volume. Transplacental transfer of 11CO to the fetal circulation is probably a minor problem due to the small fetal blood volume and the prolonged time before the same concentration is reached in the maternal and fetal blood. Measurements with 68GaCl3, which binds to transferrin, gave an intervillous space volume of 55.6% of the placental volume. The concentration of radioactivity in the placenta did not attain a steady state, indicating a clearance of the tracer from the blood only to a small extent. Measurements with 68Ga-EDTA displayed a volume of 60.4% of the placental volume. Transplacental transfer and the additional distribution of radioactivity to fetal and maternal extracellular spaces, including the placenta, when 68Ga-EDTA was used will make this tracer unsuitable in measurements of the blood volume of the placenta with PET.

Nicotinic Receptors in the CNS as Visualized by Positron Emission Tomography

Alzheimer’s disease, senile dementia of Alzheimer type (AD/SDAT) is a progressive neurodegenerative disease which entity can be described in terms of clinical symptoms, neuropsychological tests and laboratory investigations during life and postmortem histopathological examinations. For the definitive diagnosis of AD/SDAT both clinical and histopathological investigations are required. Improved diagnostic resolution is needed since there is still some lack of agreement between histopathological and clinical diagnosis. Neurochemical studies performed in autopsy or biopsy brain tissue have revealed that AD/SDAT afflicts several neurotransmitter system in the brain. Among them the cholinergic system is the one that shows the most consistent changes and also best correlates with cognitive function. Presynaptic cholinergic defects are present in autopsy AD/SDAT brain tissue such as losses in choline acetyltransferase activity, synthesis and release of acetylcholine and nicotinic receptors. Positron emission tomography (PET) is a technique suitable for in vivo studies of neuronal activity in the brain. PET has already shown a great potential for psychopharmacological research. Is it possible to study central cholinergic activity in vivo by PET? This strategy was initiated using 11C-choline (Gauthier et. al., 1985; Eckernas et al. 1985). A low penetration of intact 11C-choline to the brain combined with a rapid conversion of formed 11C-acetylcholine to labelled metabolites hampered this effort. An alternative to measuring precursor transport and transmitter turnover would be to study the cholinergic receptors in brain.