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Purpose: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro- N, N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 H-pyridazino[4,5- b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects. Methods: Here we report the radiolabelling of SSR180575 with C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats. Results: The image contrast and the binding of [C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [C]PK11195. Competition studies demonstrate that [C]SSR180575 has high specific binding for the TSPO. Conclusion: [C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic. [ABSTRACT FROM AUTHOR]

Abstract: Recently, a novel series of amidines has been described, exhibiting high NR2B-subtype selective N-methyl-D-aspartate (NMDA) antagonist activity with nanomolar or subnanomolar affinity. Within the styrylamidine subclass, (E)-N-(2-methoxybenzyl)-3-phenyl-acrylamidine (1), displayed the highest affinity (Ki=0.7nM versus [3H]ifenprodil) and was considered an appropriate candidate for isotopic labelling with carbon-11 (T 1/2: 20.38min) at its methoxy group for imaging of NMDA receptors with PET. Derivative 1 has been labelled from the corresponding nor-analogue using [11C]methyl triflate and the following experimental conditions : (1) trapping at −10°C of [11C]methyl triflate in 300μL of acetone containing 0.6–0.8mg of precursor 5 (2.4–3.2μmol) and 5μL of a 3M solution of NaOH in water (about 5eq.); (2) concentration to dryness of the reaction mixture (at 110°C, using a helium stream for 1–2min); (3) taking up the residue with 0.5mL of the HPLC mobile phase and (4) purification using semi-preparative HPLC (SymmetryPrep® C-18, Waters, 300×7.8mm). Typically, starting from a 1.5 Ci (55.5GBq) [11C]CO2 production batch, 120–240m Ci (4.44–8.88GBq) of [11C]-1 (20–40% decay-corrected radiochemical yield, ) was obtained within a total synthesis time of 25–30min. Specific radioactivities ranged from 0.8 to 1.2Ci/μmol (29.6–44.4GBq/μmol) at the end of radiosynthesis. No attempts were made to further optimise these reactions, as sufficient material was obtained to allow for preliminary pharmacological characterisation. [Copyright &y& Elsevier]

An unusual process takes place during the lithium–ammonia reduction of a variety of cyclic enones bearing an ester group in the γ-position, furnishing cyclopropanols. The reason for this unprecedented outcome has been attributed to the through-space stabilization of a developing cyclopropyl radical by interaction with the neighboring ester substituent. [Copyright &y& Elsevier]

Unlabelled: The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration., Methods: We compared PK11195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using (11)C-PK11195 or (11)C-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as (3)H-PK11195 autoradiographic studies were then correlated with the imaging data., Results: Seven days after a unilateral injection of AMPA in the striatum, (11)C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than (11)C-PK11195 (2.5-fold +/- 0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)C-DPA-713 and (11)C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, (11)C-DPA-713 uptake was significantly lower than (11)C-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for (11)C-DPA-713 than for (11)C-PK11195., Conclusion: (11)C-DPA-713 displays a higher signal-to-noise ratio than (11)C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of (11)C-DPA-713. Although further studies in humans are required, (11)C-DPA-713 represents a suitable alternative to (11)C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.