5-HT1A receptor, 5-HT2A receptor and serotonin transporter binding in the human auditory cortex in depression.

Background: Serotonergic system abnormalities are implicated in many psychiatric disorders, including major depression. The temporal lobe receives a high density of serotonergic afferent projections, and responses in the primary auditory cortex to sound are modulated by serotonergic tone. However, the associations between changes in serotonergic tone, disease state and changes in auditory cortical function remain to be clarified.

Autoradiographic Evaluation of [(18)F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain.

[(18)F]FECUMI-101 ([(18)F]1) is a 5HT1AR ligand demonstrating specific binding in brain regions corresponding to the distribution of 5-HT1AR in baboons. However, we detected moderate uptake of [(18)F]1 in baboon thalamus, a brain region lacking 5-HT1AR. We sought to investigate the relative binding of [(18)F]1 to 5-HT1AR, α1R, and 5-HT7R in vitro.

Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.

Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.

Alcoholics have more tryptophan hydroxylase 2 mRNA and protein in the dorsal and median raphe nuclei.

Background: Chronic alcohol use depletes brain serotonin (5-hydroxytryptamine [5-HT]), yet we previously found more tryptophan hydroxylase 2 (TPH2), the rate-limiting biosynthetic enzyme for 5-HT, in the dorsal raphe nucleus (DRN) of alcoholics. We sought to determine whether the increase in amount of TPH2 enzyme is associated with more TPH2 mRNA gene expression in the DRN of a new cohort of alcoholics and controls.

Methods: TPH2 mRNA and protein were measured by in situ hybridization and immunoautoradiography, respectively, in the DRN and median raphe nucleus (MRN) of age- and sex-matched pairs (n = 16) of alcoholics and nonpsychiatric controls.

Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R.

Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield.

Autoradiographic evaluation of [3H]CUMI-101, a novel, selective 5-HT1AR ligand in human and baboon brain.

[11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5-HT1AR antagonist WAY-100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY-100635.

Synthesis and in vitro evaluation of [18F](R)-FEPAQ: a potential PET ligand for VEGFR2.

Synthesis and in vitro evaluation of [(18)F](R)-N-(4-bromo-2-fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin-4-amine ((R)-[(18)F]FEPAQ or [(18)F]1), a potential imaging agent for the VEGFR2, using phosphor image autoradiography are described. Synthesis of 2, the desfluoroethyl precursor for (R)-FEPAQ was achieved from t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3) in five steps and in 50% yield. [(18)F]1 was synthesized by reaction of sodium salt of compound 2 with [(18)F]fluoroethyl tosylate in DMSO.

Synthesis, in vitro and in vivo evaluation of [11C]MMTP: a potential PET ligand for mGluR1 receptors.

Synthesis, in vitro and in vivo evaluation of [O-methyl-(11)C]dimethylamino-3(4-methoxyphenyl)-3H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-one (1), a potential imaging agent for mGluR1 receptors using PET are described. Synthesis of the corresponding desmethyl precursor 2 was achieved by demethylation of the methoxyphenyl compound 1 in 90% yield. Methylation using [(11)C]MeOTf in presence of NaOH afforded [(11)C]1 in 30% yield (EOS) with >99% chemical and radiochemical purities and with a specific activity of 3-5Ci/micromol (n=6).

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

Aim: Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [11C]R121920 and [11C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1.

Methods: PET imaging with the two novel CRF1 radioligands was performed in baboon.

Synthesis of [O-methyl-11C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide: a potential PET ligand for CB1 receptors.

Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.

Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei.

Background: Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic-pituitary-adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response.

Methods: Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO.