Binding potentials (BP_ND) of [¹¹C]PE2I.

<p>Binding potentials in the striatum (putamen and caudate) of brains of MPTP-treated and MPTP-free common marmosets are presented.</p>#1<p>:Ratios of mean daily locomotion counts of the post-MPTP period to those of pre-MPTP period (mean ± SD).</p>#2<p>:MPTP cumulative doses (mg/kg).</p>*<p>:p<0.05 against MPTP-free marmosets (Bonferroni test). SD: Standard deviation.</p

Regression lines between BP_ND, locomotion, and cumulative MPTP dose.

<p>The relationship between the binding potential (BP_ND) of [¹¹C]PE2I in the putamen or caudate and the daily locomotion count (relative to pre-MPTP counts) after cumulative MPTP administration was determined using the least squares method and is presented in the upper graphs. The relationship between BP_ND in the putamen or caudate and the cumulative MPTP dose is presented in the lower graphs.</p

Representative parametric images.

<p>Coronal sections illustrating the binding potential (BP_ND) of [¹¹C]PE2I in the brains of MPTP-free and MPTP-treated marmosets are presented.</p

Radioactivity versus time curves in the brains of MPTP-free and MPTP-treated marmosets.

<p>A dopamine transporter ligand, [¹¹C]PE2I, was intravenously administered to marmosets. The putamen and caudate in the striatum were the target regions, and the cerebellum was a reference region.</p

Development of <i>N</i>‑[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]‑<i>N</i>‑methyl-4‑[¹¹C]methylbenzamide for Positron Emission Tomography Imaging of Metabotropic Glutamate 1 Receptor in Monkey Brain

Three novel 4-substituted benzamides have been synthesized as potential ligands for the positron emission tomography (PET) imaging of metabotropic glutamate 1 (mGlu1) receptor in the brain. Of these compounds, <i>N</i>-(4-(6-(isopropylamino)­pyrimidin-4-yl)-1,3-thiazol-2-yl)-<i>N</i>,4-dimethylbenzamide (<b>4</b>) exhibited the highest binding affinity (<i>K</i>_i = 13.6 nM) for mGlu1 and was subsequently labeled with carbon-11. In vitro autoradiography using rat brain sections showed that [¹¹C]<b>4</b> binding was consistent with the distribution of mGlu1, with high specific binding in the cerebellum and thalamus. PET studies with [¹¹C]<b>4</b> in monkey showed a high brain uptake and a kinetic profile suitable for quantitative analysis. Pretreatment with a mGlu1-selective ligand <b>16</b> largely decreased the brain uptake, indicating high in vivo specific binding of [¹¹C]<b>4</b> to mGlu1. In metabolite analysis, only unchanged [¹¹C]<b>4</b> was found in the brain. [¹¹C]<b>4</b> is a useful PET ligand for the imaging and quantitative analysis of mGlu1 in monkey brain and merits further evaluation in humans

Development of Novel PET Probes for Central 2‑Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors

We document the development of PET probes for central AMPA receptors and their application to in vivo animal imaging. An initial screening of perampanel derivatives was performed to identify probe candidates. Despite the high autoradiographic contrast yielded by several radioligands, rat PET scans did not support their in vivo suitability. Further focused derivatization and a second screening by ex vivo LC-MS measurements led to the selection of 2-[1-(3-methylaminophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl]­benzonitrile, <b>21a</b>, and its analogues as candidates. [¹¹C]<b>21a</b> was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization. PET imaging with [¹¹C]<b>21a</b> demonstrated moderate uptake of radioactivity in rat and monkey brains, with the retention of radiosignals being consistent with that from the autoradiogram data, and the uptake was blocked by pretreatment with unlabeled <b>21a</b> in a dose-dependent manner. The current approach has facilitated the discovery of a PET probe potentially suitable for translational research and development focused on AMPA receptors

Development of [¹¹C]MFTC for PET Imaging of Fatty Acid Amide Hydrolase in Rat and Monkey Brains

We developed 2-methylpyridin-3-yl-4-(5-(2-fluorophenyl)-4<i>H</i>-1,2,4-triazol-3-yl)­piperidine-1-[¹¹C]­carboxylate ([¹¹C]­MFTC) as a promising PET tracer for in vivo imaging of fatty acid amide hydrolase (FAAH) in rat and monkey brains. [¹¹C]­MFTC was synthesized by reacting 3-hydroxy-2-methylpyridine (<b>2</b>) with [¹¹C]­phosgene ([¹¹C]­COCl₂), followed by reacting with 4-(5-(2-fluorophenyl)-4<i>H</i>-1,2,4-triazol-3-yl)­piperidine (<b>3</b>), with a 20 ± 4.6% radiochemical yield (decay-corrected, <i>n</i> = 30) based on [¹¹C]­CO₂ and 40 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidneys. Positron emission tomography (PET) summation images of rat brains showed high radioactivity in the frontal cortex, cerebellum, and hippocampus, which was consistent with the regional distribution pattern of FAAH in rodent brain. Pretreatment with MFTC or FAAH-selective URB597 significantly reduced the uptake in the brain. PET imaging of monkey brain showed relatively high uptake in the whole brain, particularly in the occipital cortex, which was also inhibited by treatment with MFTC or URB597. More than 96% of the total radioactivity was irreversible in the brain homogenate of rats 5 min after the radiotracer injection. The specific in vivo FAAH binding indicates that [¹¹C]­MFTC is a promising PET tracer for visualizing FAAH in the brain

Additional file 1: Supplement methods and Table S1. of Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors

Receptor binding selectivity of radioligand candidate compounds. (PDF 172 kb

Additional file 2: Figure S1. of Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors

Analytical HPLC chromatogram of [11C]TASP0410457. (PDF 527 kb

Additional file 3: Figure S2. of Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors

Analytical HPLC chromatogram of [11C]TASP0434988. (PDF 542 kb