Dimeric L-dopa derivatives as potential prodrugs

A series of dimeric derivatives (+)-1, and (+)-2, and (+)-3a-d of L-Dopa diacetyl esters was synthesized and evaluated as potential L-Dopa prodrugs with improved physicochemical properties. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of L-Dopa in human plasma was observed.     

Technetium-99m labelled integrated tropane-BAT as a potential dopamine transporter tracer

To reduce the molecular weight of 99mTc-labelled tropanes with the aim to enhance the passage over the blood-brain barrier, a so-called integrated tropane-BAT construct was developed. For this purpose a mercaptoethyl substituent was attached to the amine nitrogen atom of a nortropane precursor and the methyl carboxylate in 2beta-position was converted to a 2-mercaptoethylaminomethylene substituent. This integrated tropane-BAT construct could be labelled efficiently (85-90%) with technetium-99m. Results of LC-MS analysis of the tracer agent support the assumed structure. Biodistribution studies in normal rats (n=3) showed a slightly higher brain uptake for the new tracer agents as compared to 99mTc-TRODAT-1. These results indicate that further biological evaluation of the integrated 99mTc-tropane-BAT is warranted.     

Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration

The peripheral-type benzodiazepine receptors (PBRs) are only minimally expressed in normal brain parenchyma, where they are primarily localized in glial cells. Their basal expression rises in different neurodegenerative disorders, due to the presence of infiltrating inflammatory cells and activated microglia. [11C]PK11195, a selective PBR antagonist, has been used for the in vivo PET monitoring of neurodegeneration in clinical observations. We recently developed and labeled with carbon-11 three new carboxamide derivatives: [11C]VC193M, [11C]VC195 and [11C]VC198M. Aim of this study was to evaluate these ligands for the in vivo measuring of PBRs expression in neurodegenerations and compare their kinetic behavior with that of the reference tracer [11C]PK11195. Radioligands were evaluated in a preclinical model of Huntington's disease consisting in the monolateral striatal injection of quinolinic acid (QA). Activated microglia and astrocytic gliosis was present only within the affected striatum. A concomitant increase in radioactivity accumulation was observed for all the tracers examined (P<0.01). Among the new compounds, [11C]VC195 showed higher levels of lesioned/unlesioned striatum ratios (3.28+/-0.44), in comparison with [11C]VC193M and [11C]VC198M (2.69+/-0.53 and 1.52+/-0.36, respectively), but slightly inferior to that observed for [11C]PK11195 (3.76+/-1.41).In conclusion, the results of the study indicate that [11C]VC195 is a promising candidate for in vivo PET monitoring of neurodegenerative processes but its in vivo behavior overlap that of [11C]PK11195.     

Transition-state analogues as inhibitors of L-dopa decarboxylase

1. A series of compounds has been prepared which are analogues of the transition state of the reaction catalysed by L-dopa decarboxylase (EC 4.1.1.28). 2. These compounds are reduced adducts of the substrate (L-dopa) and coenzyme (pyridoxal phosphate), as well as analogues of these substances (D-dopa, pyridoxal and salicaldehyde). 3. Compounds were also prepared with an oxazine link between the 3'-oxygen and the nitrogen attached to the 4'-carbon of the aldehyde moiety. 4. None of the D-dopa adducts produced any significant inhibition, but the L-dopa adducts were all active at millimolar levels, with the oxazine derivatives being more active than their parent compounds. 5. Inhibition was competitive with respect to L-dopa, but was neither competitive nor non-competitive with respect to pyridoxal phosphate. 6. The most active compound tested was the oxazine derivative of the L-dopa/salicaldehyde adduct, with an estimated Ki of 58.0 microM. 7. Increased inhibitory activity was observed when enzyme depleted of pyridoxal phosphate was used.     

Measurement of o- and m-tyrosine as markers of oxidative damage in motor neuron disease

Abstract

Oxidative damage is thought to play an important role in many disease states. Damage caused by reactive oxygen species has been linked to degenerative conditions such as cancer, atherosclerosis, inflammatory disease, lens tissue disease, Alzheimer's disease and motor neurone disease, as well as to the aging process itself. Damage could arise through increased levels of reactive species or through alterations in levels of free radical scavenger molecules such as superoxide dismutase.     

Synthesis of a potential photoactivatable anandamide analog

A potential photoreactive analog of anandamide was synthesized via selective hydrogenation of a skipped tetrayne intermediate. This compound might be a useful tool to search for new cannabinoid receptors.     

Parallel solid-phase synthesis and characterization of new sulfonamide and carboxamide proline derivatives as potential CNS agents

A solid-phase synthesis of the 64-member library of novel sulfonamide and carboxamide proline derivatives, focused on the 5-HT7 receptor antagonist SB-258741, was described. The final compounds were obtained in good yields and high purity upon cleavage from SynPhase Lanterns, functionalized by a BAL linker. The library representatives were screened for 5-HT7, 5-HT1A and D2 receptors to explore the impact of a tertiary amine moiety, the length of an alkylene spacer and the aryl fragment on the receptor affinity. The preliminary biological results provided data for further investigation aimed at a search for 5-HT7 receptor agents, and permitted the identification of several compounds with significant 5-HT1A receptor affinity.     

Adenosine uptake site heterogeneity in the mammalian CNS? Uptake inhibitors as probes and potential neuropharmaceuticals

Inhibitors of adenosine uptake or transport have been used clinically for some time in certain cardiovascular diseases. More recently, some of them have also been investigated for possible clinical use in combination with antimetabolites based on the observed heterogeneity of nucleoside transport in mammalian tumor cells. Such a heterogeneity of adenosine uptake and uptake sites has now also been suggested in the mammalian CNS. The aim of this article is, therefore, to review the present status of our knowledge of adenosine uptake in the mammalian CNS, compare it with our far more advanced knowledge of nucleoside transport in other mammalian cells and suggest direction of future research. The possible implications for the development of adenosine uptake inhibitors as adenosinergic neuropharmaceuticals will be discussed based on our knowledge of the physiological function of adenosine in the CNS.     

Animal status as a response to pet owner experience

Abstract

It has been reported that pet ownership has positive effects on people's attitudes to other animals. It was, however, hypothesized in this study that it is the good experiences which bring this about and that bad ones would have negative effects. Two sections in a 21-section questionnaire investigated whether this is the case. Respondents described their experiences with pets. They reported their level of agreement on seven philosophical/theological quotations reflecting contrasting views of animal status, and on five specific uses to which non-pet animals are put. The hypothesis was partly supported, in that while good experiences did make a statistically significant difference, bad or sad ones did not.     

Small pet aquarium frogs as a source of salmonella

[This corrects the article on p. 1027 in vol. 33.].     

Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors

EMPA is a selective antagonist of orexin 2 (OX₂) receptors. Previous literature with [³H]-EMPA suggest that it may be used as an imaging agent for OX₂ receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [¹¹C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([¹¹C]EMPA), and evaluation as a potential PET tracer for OX₂ receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [¹¹C]CH₃I in the presence of cesium carbonate in DMSO at room temp afforded [¹¹C]EMPA in 1.5–2.5% yield (non-decay corrected relative to trapped [¹¹C]CH₃I at EOS) with ?95% chemical and radiochemical purities. The total synthesis time was 34–36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [¹¹C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.     

Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-dopa

The synthesis and in vitro chemical and enzymatic stability of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine (9) as L-Dopa prodrug are described. Prodrug 9 possesses a good lipophilicity (log P = 2.153 +/- 0.017), is stable in aqueous buffer solutions (pH 1.3 and 7.4), and in 80% rat and human plasma it is turned into L-Dopa.     

Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter

The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labeling with PET isotopes, were synthesized and evaluated as SERT ligands. The chemistry of these novel derivatives, their biological evaluation, the general method of preparing the precursor indole for labeling, and the C-11 labeling of the most promising indole derivative, are described herein.     

Small pet aquarium frogs as a source of Salmonella.

Salmonellae were isolated from 21% of the samples of freshwater aquarium frogs tested and from 25% of the samples of aquarium water containing these frogs. The salmonellae were Salmonella arizonae, S. bovis-morbificans, S. hadar, S. saint-paul, S. typhimurium, and S. worthington. These isolations were made over a period of 9 months and from three different cities. This association of salmonellae with frogs may contribute to cases of human salmonellosis since other aquarium species have already been shown to contribute to such cases.