title: (-)-N-[(11)C]propyl-norapomorphine: a positron-labeled dopamine agonist for PET imaging of D(2) receptors.
abstract: Imaging neuroreceptors with radiolabeled agonists might provide valuable information on the in vivo agonist affinity states of receptors of interest. We report here the radiosynthesis, biodistribution in rodents, and imaging studies in baboons of [(11)C]-labeled (-)-N-propyl-norapomorphine [(-)-NPA]. (-)-[(11)C]NPA was prepared by reacting norapomorphine with [(11)C]propionyl chloride and a lithium aluminum hydride reduction. [(11)C]Propionyl chloride was prepared by reacting [(11)C]CO(2) with ethylmagnesium bromide, followed by reacting with phthaloyl chloride. The radiochemical yield of (-)-[(11)C]NPA was 2.5% at end of synthesis (EOS), and the synthesis time was 60 min. The specific activity was 1700+/-1900 mCi/micromol ( N=7; ranged 110-5200 mCi/micromol at EOS). Rodent biodistribution studies showed high uptake of [(11)C](-)-NPA in D(2) receptor-rich areas, and the striatum/cerebellum ratios were 1.7, 3.4, and 4.4 at 5 min, 30 min, and 60 min postinjection, respectively. Pretreating the animals with haloperidol (1 mg/kg) decreased the striatum/cerebellum ratio at 30 min postinjection to 1.3. (-)-[(11)C]NPA was also evaluated via baboon positron emission tomography (PET) studies. Under control conditions ( N=4), rapid uptake of the tracer was observed and the striatum/cerebellum ratio reached 2.86+/-0.15 at 45 min postinjection. Following haloperidol pretreatment (0.2 mg/kg IV), the striatum/cerebellum ratio was 1.29 at 45 min postinjection. The result demonstrated the existence of specific binding of this new tracer to the D(2) receptor. To our knowledge, the current finding of a striatum/cerebellum ratio of 2.8 in baboon was the highest reported with a radiolabeled D(2) agonist. (-)-[(11)C]NPA is a promising new D(2) agonist PET tracer for probing D(2) receptors in vivo using PET.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, New York, USA. hwang@neuron.cpmc.columbia.edu
authors.forename: D R
authors.initials: DR
authors.lastname: Hwang
authors.forename: L S
authors.initials: LS
authors.lastname: Kegeles
authors.forename: M
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000737:chemistry; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D009942:Organometallic Compounds / Q000737:chemistry; D010215:Papio; D011422:Propionates / Q000737:chemistry; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009942:Organometallic Compounds; D011422:Propionates; D011849:Radioactive Tracers; D017448:Receptors, Dopamine D2; C008668:norapomorphine; C009074:N-n-propylnorapomorphine; C417902:propanoyl chloride; D006220:Haloperidol; D001058:Apomorphine