Philip H. Elsinga

Small-Animal PET Study of Adenosine A 1 Receptors in Rat Brain: Blocking Receptors and Raising Extracellular Adenosine

Activation of adenosine A1 receptors (A1R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A1R can be visualized using 8-dicyclopropylmethyl-1-11C-methyl-3-propyl-xanthine (11C-MPDX) and PET. This study aims to test whether 11C-MPDX can be used for quantitative studies of cerebral A1R in rodents. Methods: 11C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A1R, whereas ethanol and ABT-702 increase extracellular adenosine. Results: In groups 1 and 3, the brain was clearly visualized. High uptake of 11C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%–45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K1/k2 from the model fit) was not altered under the study conditions. Conclusion: 11C-MPDX shows a regional distribution in rat brain consistent with binding to A1R. Tracer binding is blocked by the selective A1R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases 11C-MPDX uptake. This increase may reflect an increased availability of A1R after acute exposure to ethanol.

Carbon-11 Labeled Tyrosine as a Probe for Modelling the Protein Synthesis Rate

L-[1-11C]tyrosine was used to measure the protein synthesis rate in two tumor models in rats. Dynamic PET-data were acquired using a double headed scintillation camera system operated in a coincidence mode. From blood samples the plasma concentration of L-[1-11C]tyrosine was measured as a function of time. A four compartment model was used to analyze the data. The unique solutions for the two different tumor models showed a significant difference in protein synthesis rate.

Carbon-11 Amino Acids, Labeling and Metabolites

The preparation methods available for HC-amino acids and the different aspects of the value of these amino acids for measuring the protein synthesis rate in vivo are disxad cussed.

Development and production of radiopharmaceuticals for PET

Short-lived labelled positron emitting radionuclides are mainly applied for the non invasive investigation of regional biochemistry, physiology, effect of therapy and for the pharmacokinetics of drugs in the human body by positron emission tomography (PET). PET is gradually transforming from a purely research modality into one of mainstream clinical practice.