Dopaminergic function and dopamine transporter binding assessed with positron emission tomography in Parkinson disease.

Background: Measuring progression of Parkinson disease (PD) using positron emission tomography may help demonstrate the efficacy of neuroprotective treatments. To date, (18)F-dopa has been the gold standard to measure presynaptic dopaminergic function in PD, but this tracer might overestimate the rate of neuronal death in PD because its uptake also depends on dopamine turnover rather than exclusively on the density of dopaminergic terminals in the striatum. The latter might be assessed using newly developed ligands of the membrane dopamine transporter.

Synthesis and biodistribution of two potential PET radioligands for dopamine reuptake sites: no-carrier-added 4-(2-[18F]fluoroethyl) and 4-[11C]methyl BTCP-piperazine.

Radioligands that specifically target dopamine uptake sites can provide a means of determining dopamine fiber loss at intrastriatal mesencephalic grafts in Parkinsonian patients, using Positron Emission Tomography (PET). The BTCP derivative, 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-(2-hydroxyethyl)-piperazine, shows in vitro high affinity and selectivity for the dopamine transporter. To evaluate the potential of such a compound as a potential dopaminergic PET tracer the positron-emitting analogues, 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-(2-[18F]fluoroethyl)-piperazine and 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-[11C]methylpiperazine, were synthesized.

Synthesis of [3',5'-3H2]-alpha-fluoromethyl-tyrosine as a radioactive specific label of rat brain tyrosine hydroxylase.

The [3',5']-ditritio-alpha-fluoromethyl-tyrosine 4 (specific activity 15.0 Ci/mmol) has been synthesized and used as a radioactive probe for rat neuronal tyrosine hydroxylase (TH). The route of synthesis for the preparation of 3 and 4 allowed us to not only introduce a fluorine atom into 3/4 using an inorganic source of fluorine (CsF), but also to take advantage of the high-yielding cyclization of (alpha,beta)-acetamido alcohols mediated by diethylaminosulfur trifluoride (DAST) to give the corresponding oxazolines.

Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons.

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18F-positron-emitting analogue of 3-fluoromethyl-1-[1-(2-benzothienyl)-cyclohexyl]-piperidine, [18F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. [18F]BTCP was obtained from cyclotron-produced n.c.

Binding properties of 3-[125I]iodophencyclidine, a new radioligand for N-methyl-D-aspartate-gated ionic channels.

The binding properties of the 125I-labeled phencyclidine derivative N-[1-(3-[125I]iodophenyl)cyclohexyl]piperidine (3-[125I]iodo-PCP), a new ligand of the N-methyl-D-aspartate (NMDA)-gated ionic channel, were investigated. Association and dissociation kinetic curves of 3-[125I]iodo-PCP with rat brain homogenates were well described by two components. About 32% of the binding was of fast association and fast dissociation, and the remaining binding was of slow association and slow dissociation.

[3H]RP 62203, a ligand of choice to label in vivo brain 5-HT2 receptors.

There are only a few ligands available for labelling brain receptors simply because in vivo binding requires more severe experimental conditions than in vitro binding. We now describe the in vivo binding properties of [3H]RP 62203, a new potent and selective 5-HT2 antagonist. After intravenous injection into rats, [3H]RP 62203 accumulated predominantly in brain regions containing 5-HT2 receptors, with a frontal cortex/cerebellum ratio of 6 to 7.

Quantitative autoradiographic mapping of 5-HT3 receptors in the rat CNS using [125I]iodo-zacopride and [3H]zacopride as radioligands.

Substitution of the chlorine atom by a radio-iodine in position 5 in the zacopride molecule yielded [125I]iodo-zacopride that bound with high affinity (Kd = 4.3 nM) to 5-HT3 receptors in the rat central nervous system. Assays with membranes from the posterior (mainly entorhinal) cortex confirmed that the pharmacological properties and regional distribution of [125I]iodo-zacopride-specific binding sites were identical with those of 5-HT3 sites labelled by the reference radioligand [3H]zacopride.

[(125I)iodo-zacopride: new ligand for the study by autoradiography of central 5-HT3 receptors].

This paper describes the synthesis and the pharmacological characteristics of the first radioiodinated ligand of central 5-HT3 receptors: [125I]iodo-zacopride. Specific sites having a high affinity (Kd = 4.3 nM) for [125I]iodo-zacopride have been found in membranes from the rat entorhinal cortex.

Chromatographic analyses of the serotonin 5-HT1A receptor solubilized from the rat hippocampus.

Serotonin 5-HT1A receptors in rat hippocampal membranes were solubilized by 10 mM 3-[3-(cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS) and chromatographed on various gels in an attempt to design a relevant protocol for their (partial) purification. In particular, an affinity gel made of the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) derivative 8-methoxy-2-[(N-propyl, N-butylamino)amino]tetralin (8-MeO-N-PBAT) coupled to Affigel 202 was specially developed for this purpose. First, studies of the effects of various compounds (detergents, lipids, reducing agents, sugars, etc.

[125I-BH-8-MeO-N-PAT, a new ligand for the study of 5-HT1A receptors in the central nervous system].

Specific radioactive ligands are needed for studying the pharmacological properties and the regional distribution of the different classes of 5-HT1 receptors within the central nervous system. We describe here the synthesis and some characteristics of the first iodinated specific ligand of 5-HT1A receptors. Like its parent compound, the agonist 8-hydroxy-2-(di-n-propylamino)tetralin or 8-OH-DPAT, [125I]-BH-8-MeO-N-PAT, exhibits a high affinity and excellent selectivity for 5-HT1A sites.