Regional distribution of the opioid receptor agonist N-(methyl-11C)pethidine in the brain of the rhesus monkey studied with positron emission tomography.

The regional distribution and kinetics in the brain of Rhesus monkeys of N-(methyl-11C)-pethidine have been studied by positron emission tomography, PET. 11C-Pethidine reached the brain with peak radioactivities appearing within 6-10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7-3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors using in vitro binding techniques. The 11C-pethidine derived radioactivity left the brain with an initial half-life of 40-60 min., followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sites. By the use of a three-compartment model, it was possible to get an estimate of 11C-pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax./Kd, was 0.06-0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of 11C-pethidine is mainly determined by its blood kinetics.

Brain and plasma kinetics of the opioid 11C-hydromorphone in two macaque species.

The regional brain kinetics of the opioid receptor agonist, hydromorphone, labelled with 11C, were studied with positron emission tomography in two Macaque species. Rhesus and Cynomolgus monkeys. The plasma kinetics of 11C-hydromorphone was simultaneously determined. Rapid plasma elimination was obvious in both monkey species. Brain radioactivity was generally low in both, but 1.4 times higher in the Rhesus than in the Cynomolgus monkey brain. This observation might explain the more rapid development of tolerance in the Rhesus monkey.

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography.

In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C-nomifensine was administered i.v. in trace amounts (10-50 micrograms) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the time-course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

Synthesis of L- and D-[methyl-11C]methionine.

This report describes the synthesis of L- and D-[methyl-11C]methionine in pure enantiomeric forms. The compounds were prepared routinely approximately 1,000 times with less than 20 failures. Starting with carbon-11 (11C) methyl iodide, a simple one-carbon precursor produced from a one-pot or a two-pot apparatus, L- and D-[methyl-11C]methionine were prepared, respectively, with an optical purity higher than 99% in 40%-90% radiochemical yields. The total time for synthesis, starting from [11C]carbon dioxide, was 12-15 min. The crude product usually had a radiochemical purity greater than 95%. The total time for synthesis, including LC purification, was 20-30 min. The radiochemical purity of the product in each case was greater than 98%.

Influence of monoamine oxidase inhibitors and a dopamine uptake blocker on the distribution of 11C-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 11C-MPTP, in the head of the rhesus monkey.

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, is a neurotoxic substance known to induce a parkinsonian syndrome in primates. The distribution of intravenously injected 11C-labelled MPTP (11C-MPTP) in the head of Rhesus monkeys was studied by means of positron emission tomography, PET. The influence of pretreatment with two monoamine oxidase (MAO) inhibitors, namely pargyline and clorgyline, and a dopamine uptake blocker, nomifensine, on the distribution was also evaluated. The 11C-radioactivity was taken up in all brain regions and maximum radioactivities were found 3-8 min after intravenous administration of MPTP. The 11C-MPTP-derived radioactivity showed a constant value throughout the study period in areas corresponding to the striatum and mesencephalon in monkeys not pretreated and in monkeys pretreated with clorgyline and with nomifensine. Pargyline pretreatment, however, resulted in consecutive elimination of 11C-MPTP-derived radioactivity from the different brain regions with half-lives of 40-60 min. The total radioactivity in blood was also higher after pargyline pretreatment indicating successful inhibition of metabolism. The eyes and temporal muscle each showed radioactivity values of the same order in all monkeys irrespective of pretreatment. The results support findings by other authors that MPTP was rapidly converted in the brain to a reactive metabolite which concentration remained constant in the brain during the PET study. Pargyline in the dosage used is known to be a non-selective MAO inhibitor and it prevented the metabolism of 11C-MPTP to the products retained in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)