This chapter focuses on attempts to measure cholinergic markers (acetylcholine synthesis, muscarinic and nicotinic receptors) in brain by the Positron Emission Tomography (PET) technique with special reference to Alzheimer's disease. Information about the cholinergic system in the human brain has mainly been obtained from neurochemical studies performed in autopsy but rarely also in biopsy brain tissue. The neurochemical analysis have mainly been restricted to measurement of enzyme activities (acetylcholinesterase, choline acetyltransferase) and cholinergic muscarinic and nicotinic receptor densities. The PET technique is therefore of interest as a putative diagnostic tool in neurodegenerative diseases such as Alzheimer's disease. Neurochemical studies in postmortem brain tissue from Alzheimer patients have revealed a marked deficit of the cortical nicotinic receptors. By using PET it is now possible to visualize receptor binding in human brain in vivo. For the cholinergic system in brain receptor studies using PET might be one way to visualize tracers for cholinergic function in brain.

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.

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.

The underlying cause of long-term complications of l-DOPA therapy in Parkinson's disease is largely unknown. Recently, centrally and peripherally acting catechol-O-methyltransferase (COMT) inhibitors became available. These drugs are capable of inhibiting the generation of 3-O-methyl-DOPA (3-OMD), a major metabolite of l-DOPA developing considerable plasma levels during l-DOPA therapy. The use of these drugs offers the opportunity to study the involvement of 3-OMD in the development of behavioral supersensitivity following repeated doses of l-DOPA over 11 days in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic system. Repeated daily administration of l-DOPA/Carbidopa produced continuous increase of contralateral rotations to both l-DOPA/Carbidopa and to challenge doses of apomorphine. This increase was not influenced by peripherally and peripherally plus centrally acting COMT inhibitors, OR-462 and OR-486, respectively, administered simultaneously with l-DOPA/Carbidopa. Both COMT inibitors suppressed the l-DOPA induced increase of 3-OMD plasma levels, OR-486 being more effective than OR-462. This indicates that 3-OMD is not involved in the development of behavioral supersensitivity following repeated l-DOPA treatment in rats with unilateral 6-OHDA lesion of the nigrostriatal system.

The future impact of positron emission tomography in clinical and basic sciences will be closely related to further developments of detector systems with regard to sensitivity and resolution, but probably even more with respect to developments in the synthesis of relevant labeled tracer molecules. Among the interesting radionuclides, 11C is of special interest since it is a radionuclide of an element, carbon, frequently occurring in the biosystem. In this paper some of the recent progress within the field of using the short-lived radionuclide 11C with a half-life of 20.4 min is presented. The paper deals with synthetic strategies which have been applied starting from simple one-carbon precursors like 11C carbon dioxide. In these strategies the development of reliable methods for production of one-carbon and multiple-carbon precursors, as well as multiple-carbon difunctional precursors, is important. Some examples are discussed. Labeled precursors can be applied conventional types of organic synthesis, in enzyme catalyzed reactions, or by using a combination of these. The synthesis of interesting 11C labeled receptor ligands and amino acids such as alanine, valine, phenylalanine, DOPA, tryptophan, 5-hydroxytryptophan, 2-methyltyrosine and some neuropeptides are presented.

Positron 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.

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.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 26, Issue 1-12 p. 409-411 Symposium Abstract Synthesis of racemiry, (+) and (-) N-(methyl-11C) nomifensine, a ligand for evaluation of monoamine reuptake sites by PET J. Ulin, J. Ulin Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this authorA.D. Gee, A.D. Gee Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this authorP. Malmborg, P. Malmborg The Svedberg Laboratory, University of Uppsala, Uppsala, SwedenSearch for more papers by this authorB. Långström, B. Långström Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this author J. Ulin, J. Ulin Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this authorA.D. Gee, A.D. Gee Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this authorP. Malmborg, P. Malmborg The Svedberg Laboratory, University of Uppsala, Uppsala, SwedenSearch for more papers by this authorB. Långström, B. Långström Department of Organic Chemistry, Institute of Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, SwedenSearch for more papers by this author First published: January 1989 https://doi.org/10.1002/jlcr.25802601176Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume26, Issue1-12January 1989Pages 409-411 RelatedInformation

N-[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.

The potential value of positron emission tomography (PET) in evaluating the myocardial energy metabolism was studied in two previously healthy mini-pigs before, during and after the induction of non-insulin dependent diabetes with alloxan. The distribution and kinetics of radioactivity derived from trace amounts of 11C-pyruvate and 1-11C-palmitate were followed in different sections of the myocardium. The early distribution of both tracers was similar even after the development of diabetes. The elimination of 11C-pyruvate derived radioactivity was slower in the diabetic heart. The rate of beta-oxidation was also decreased as suggested by the elimination curve of 11C-palmitate and the incorporation of 11C-palmitate into the triglyceride and phospholipid pool of the myocardium was increased in the diabetic animals. The results are consistent with previous observations using other techniques. Positron emission tomography offers the opportunity to characterize regional tissue metabolism quantitatively in vivo. This method may become a powerful tool in studying myocardial metabolism and the metabolic basis for the cardiac dysfunction in diabetes mellitus.

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.

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.