UNLABELLED: D2 dopamine receptors in extrastriatal brain regions are of central interest for research in schizophrenia and antipsychotic drugs. This article reports the development of [11C]FLB 457 for PET examination of extrastriatal D2 dopamine receptors. METHODS: Carbon-11-FLB 457 was prepared by O-methylation of FLB 604 (2-hydroxy precursor) with [11C]methyl iodide. Total radiochemical yield was 25%-35% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was about 1300 Ci/mmole (48 GBq/mumole). RESULTS: FLB 457 bound with high affinity to D2 and D3 dopamine receptors, whereas binding to other putative central receptors was negligible. PET studies in Cynomolgus monkeys demonstrated 15 times higher accumulation of radioactivity in the striatum than in the cerebellum after 60 min. Uptake in the thalamus and neocortex, extrastriatal regions with a low density of D2 dopamine receptors, was, respectively, 4 and 2.5 times higher than in the cerebellum. Radioactivity was displaced by raclopride and haloperidol which confirms the selectivity and reversibility of [11C]FLB 457 binding to D2 dopamine receptors in vivo in the striatum, thalamus and neocortex. CONCLUSION: Carbon-11-FLB 457 should be a useful PET ligand for quantitative examination of D2 dopamine receptors in extrastriatal regions in the human brain.

Animals↗

PubMed1994

Preparation of a potential positron emission tomographic radioligand for the dopamine transporter.

NNC 12-0722 (1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%-50% with an overall synthesis time of 30-35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.

Animals↗

PubMed1994

Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart.

(-)-Norepinephrine is the predominant neurotransmitter of the sympathetic innervation of the heart. Racemic norepinephrine was labelled with carbon-11 and injected i.v. into Cynomolgus monkeys. Five minutes after injection there was a more than tenfold higher radioactivity in the heart than in adjacent tissue. Pretreatment with the norepinephrine reuptake inhibitor desipramine reduced the uptake by more than 80%. The high specific uptake of racemic [11C]norepinephrine indicates that enantiomerically pure (-)-[11C]norepinephrine has promising potential for detailed mapping of the sympathetic innervation of the human myocardium.

Animals↗

PubMed1994

Selective synthesis of racemic 1-11C-labelled norepinephrine, octopamine, norphenylephrine and phenylethanolamine using [11C]nitromethane.

A new and simple method for the selective condensation of no-carrier-added [11C]nitromethane (1) with various substituted (protected) benzaldehydes to [beta-11C]beta-nitrophenethyl alcohols was developed. This method which utilizes tetrabutylammonium fluoride in THF as a catalyst gave a condensation yield of 80-90% and a selectivity of 80-90% for [11C]nitroalcohol vs [11C]nitrostyrene formation within 2 min. Reduction of these [11C]nitroalcohols with Raney nickel in formic acid gave the corresponding [11C]aminoalcohols in a yield of 60-90%. Boron tribromide was used for the cleavage of 4-methoxy and 3,4-(methylenedioxy) phenol protecting groups. After HPLC-purification, racemic 1-11C-labelled norepinephrine (7), phenylethanolamine (4), norphenylephrine (5) and octopamine (6) were prepared in a 12-30% decay corrected total radiochemical yield (20-50% counted from 1) with an overall synthesis time of 40-70 min from end of bombardment (EOB). The radiochemical purity was > 98% and the specific radioactivity 700-1500 Ci/mmol (26-56 GBq/mumol).

2-Hydroxyphenethylamine↗

PubMed1993

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor.

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with 11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor.

Adult↗

PubMed1993

Preparation of [1-11C]dopamine, [1-11C]p-tyramine and [1-11C]m-tyramine. Autoradiography and PET examination of [1-11C]dopamine in primates.

A method for no-carrier-added 1-11C-labelling of 3-hydroxy-, 4-hydroxy- and 3,4-dihydroxy-substituted phenethylamines is described. [11C]Dopamine, [11C]p-tyramine and [11C]m-tyramine were prepared from on-line produced [11C]nitromethane. Condensation of [11C]nitromethane with various protected and unprotected benzaldehydes was investigated. A one-pot two-step reduction of the substituted 11C-labelled nitrostyrene intermediates, gave after hydrolysis and reversed-phase semi-preparative HPLC-purification the corresponding labelled amines in a total radiochemical yield of 8-20% (based on [11C]CO2 and decay-corrected). The total synthesis time was 45-50 min with a specific radioactivity of 400-1000 Ci/mmol (15-37 GBq/mumol). The radiochemical purity was higher than 98% [11C]Dopamine was used for in vitro autoradiography on human post-mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. Autoradiographic examination of [11C]dopamine binding on human brain section post-mortem demonstrated specific binding in the caudate putamen and the substantia nigra, regions with a dense dopaminergic innervation. Some binding was also seen in the globus pallidum, nucleus ventralis of the thalamus and in nucleus dentatus of the cerebellum, regions where the dopaminergic innervation is very low. In PET examinations of [11C]dopamine binding in Cynomolgus monkeys there was a high uptake of radioactivity in the pituitary, the kidneys and the heart. Any passage of [11C]dopamine across the blood-brain barrier could not be demonstrated. In human PET studies [11C]dopamine has potential as a radioligand for examination of the myocardium, pituitary and kidneys.

Animals↗

PubMed1993

[11C] beta-CIT, a cocaine analogue. Preparation, autoradiography and preliminary PET investigations.

beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) is a cocaine analogue with a high affinity for the dopamine transporter. [11C] beta-CIT was prepared by N-methylation of nor-beta-CIT with [11C]methyl iodide. The total radiochemical yield of [11C] beta-CIT was 40-50% with an overall synthesis time of 35-40 min. The radiochemical purity was > 99% and the specific radioactivity at the time of injection was about 1000 Ci/mmol (37 GBq/mumol). Autoradiographic examination of [11C] beta-CIT binding in human brains post-mortem demonstrated a high level of specific binding in the striatum. PET examination of [11C] beta-CIT in a Cynomolgus monkey showed a marked accumulation of radioactivity in the striatum. The ratio of radioactivity in the striatum-to-cerebellum approached 5 after 87 min. In a displacement experiment, radioactivity in the striatum but not in the cerebellum, was markedly reduced after injection of unlabelled cocaine. [11C] beta-CIT has a potential as ligand for PET examination of cocaine effects in man.

Animals↗

PubMed1993

[11C]NNC 687 and [11C]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investigation in monkey.

NNC 687 and NNC 756 [(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl- 8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine and (+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine] are two new potent dopamine D-1 receptor antagonists. [11C]NNC 687 and [11C]NNC 756 were both prepared by N-methylation of the corresponding desmethyl compounds with [11C]methyl iodide. The reactions were performed in acetone with subsequent normal-phase semi-preparative HPLC and resulting in 50-60% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min and a radiochemical purity higher than 99%. The specific radioactivity obtained at time of injection was about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 687 and [11C]NNC 756 binding in post-mortem human brain sections showed specific binding in the striatum, a region with high density of dopamine D-1 receptors. PET examination of the radioligands in a Cynomolgus monkey demonstrated accumulation of radioactivity predominantly in the striatum. The ratio between radioactivities in the striatum and the cerebellum was about 2 and 8 for [11C]NNC 687 and [11C]NNC 756 after 60 min. [11C]NNC 756 should have potential as PET ligand for examination of central dopamine D-1 receptors in man.

Alkylation↗

PubMed1992

PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.

Adult↗

PubMed1992

(S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET.

In order to investigate [11C]nicotine binding and metabolism in the living human brain by PET, routine protocols were developed for the preparation and purification of (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. (S)- and (R)-[11C]nicotine were prepared by N-methylation with [11C]methyl iodide of the appropriate secondary amine, which was liberated in situ by 2,2,6,6,-tetramethylpiperidine (TMP) from its corresponding biscamsylate-salt. (R/S)-[11C]Cotinine was prepared by N-methylation of the amide precursor using tetrabutylammonium hydroxide as a phase transfer catalyst. Straight-phase semipreparative HPLC was in all purifications found to be superior to reversed-phase since the contamination by the norcompounds was eliminated. Reaction in acetonitrile for both (S)- and (R)-[11C]nicotine (5 min, 130 degrees C) and (R/S)-[11C]cotinine (1 min, 80 degrees C) with subsequent straight-phase HPLC purification resulted in 35-45% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min, a specific radioactivity of 1000-1500 Ci/mmol (37-55 GBq/mumol, EOS) and a radiochemical purity > 99%. The uptake and distribution of these tracers in the human brain was studied in healthy volunteers by PET. The metabolite (R/S)-[11C]cotinine did not cross the blood-brain barrier to any significant degree. The amount of the total radioactivity representing (S)-[11C]nicotine measured in plasma by HPLC was 75% at 4 min and 25% at 50 min.

Brain↗

PubMed1991

Autoradiography with saturation experiments of 11C-Ro 15-1788 binding to human brain sections.

In vitro autoradiography of a 11C-labelled ligand, Ro 15-1788, was used in saturation experiments in order to quantify benzodiazepine receptor binding in whole human brain hemisphere cryo-sections. A special incubation chamber was developed with the aim of performing standardized quantitative studies with short-lived positron emitting isotopes. 11C-labelled ligand binding was studied in temporal cortex, cerebellum, white manner and pons incubated in vitro. White manner, lacking benzodiazepine receptor binding, was used as an estimated of nonspecific binding, for calculation of Saturability of binding was demonstrated in the neocortical and cerebellar regions. Radioactivity counting of incubated adjacent tissue sections was done as a control. Computerized densitometry of the autoradiograms gave similar results as the tissue counting. A comparison with in vivo saturation experiments using the same 11C-labelled ligand and positron emission tomography in healthy human subjects also gave binding characteristics of the same magnitude. The 11C-autoradiograms showed a good spatial resolution (about 180 microns). 11C-autoradiography with suitable radioligands should be a valuable technique of screening the distribution and characteristics of neuroreceptors in the human brain. This quantitative method will provide the PET investigator with preliminary binding data, and may thus supply valuable information concerning positioning in PET and concerning significant regions of interest.

Autoradiography↗

PubMed1991

Autoradiography and saturation experiments with 11C-RO 15-1788 binding to human brain.

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Autoradiography↗