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Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N , N -dimethyl-2-(2-amino-4-[ 18 F]fluorophenylthio)benzylamine (4-[ 18 F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.

Purpose: The aim of this study was to assess the feasibility of using 4-[F]-ADAM as a brain SERT imaging agent in humans. Methods: Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33 ± 9 years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region. Results: 4-[F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN) > TH > STR > PFC > CB. The DVR ( n = 4, t* = 60 min) in the RN, TH, STR and PFC were 3.00 ± 0.50, 2.25 ± 0.45, 2.05 ± 0.31 and 1.40 ± 0.13, respectively. The optimal time for imaging brain SERT with 4-[F]-ADAM was 120-140 min after injection. At the optimal imaging time, the SURs ( n = 15) in the MB, TH, STR, and PFC were 2.25 ± 0.20, 2.28 ± 0.20, 2.12 ± 0.18 and 1.47 ± 0.14, respectively. There were no significant differences in SERT availability between men and women ( p < 0.05). Conclusion: The results of this study showed that 4-[F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[F]-ADAM may be feasible for assessing the status of brain SERT in humans. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine (METH)-associated alterations in the striatal dopamine (DA) system or dopamine transport (DAT) have been identified in clinical and preclinical studies with positron emission tomography (PET) imaging but have not been well correlated with in vivo serotonin transporter (SERT) availability due to the lack of appropriate imaging agents to assess SERTs. N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM) has been developed by our group and validated for its high affinity and selectivity for SERTs, allowing the in vivo examination of SERT density, location, and binding function. The aims of this study were to investigate the potential of SERT imaging using 4-[18F]-ADAM PET to estimate the long-lasting effects of METH-induced serotonergic neurotoxicity, and further determine whether a correlative relationship exists between SERT availability/activity and tyrosine hydroxylase (TH) activity in various brain regions due to the long-lasting consequences of METH treatment. Results: Male rats received four administrations of METH (5 or 10 mg/kg, s.c.) or saline (1 ml/kg, s.c.) at 1-h intervals. At 30 days post-administration, in vivo SERT availability and activity were measured by 4-[18F]ADAM PET imaging. In contrast to the controls, the uptake of 4-[18F]ADAM in METH-treated mice was significantly reduced in a dose-dependent manner in the midbrain, followed by the hypothalamus, thalamus, striatum, hippocampus, and frontal cortex. The regional effects of METH on TH activity were assessed by quantitative immunohistochemistry and presented as integrated optical density (IOD). A significant decrease in TH immunostaining and IOD ratios was seen in the caudate, putamen, nucleus accumbens, substantia nigra pars compacta, and substantia nigra pars reticulata in the METH-treated rats compared to controls. Conclusion: The present results suggested that the long-lasting response to METH decreased the uptake of 4-[18F]-ADAM and varied regionally along with TH immunoreactivity. In addition, 4-[18F]ADAM PET could be used to detect serotonergic neuron loss and to evaluate the severity of serotonergic neurotoxicity of METH. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT. [ABSTRACT FROM AUTHOR]

Abstract: 3, 4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague–Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[18F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[18F]-ADAM sites was measured. Specific 4-[18F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55–75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30–50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40–75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[18F]-ADAM micro-PET. [Copyright &y& Elsevier]

Graphical abstract Abstract The 3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, which ultimately leads to serotonergic (5-HT) neurotoxicity and psychiatric disorders. Previous in vitro studies have consistently demonstrated that MDMA provokes autophagic activation, as well as damage of 5-HT axons and nerve fibers. So far, whether autophagy, a well-conserved cellular process that is critical for cell fate, also participates in MDMA-induced neurotoxicity in vivo remains elusive. Here, we first examined time-course of autophagy-related changes during repeated administration of MDMA (10 mg/kg s.c. twice daily for 4 consecutive days) using immunofluorescent staining for tryptophan hydroxylase and microtubule-associated protein 1 light chain 3 beta in rats. We also evaluated the protective effects of 3-methyadanine (3-MA, an autophagy inhibitor, 15 mg/kg i.p.) against MDMA-induced acute and long-term reductions in serotonin transporters (SERT) density in various brain regions using immunohistochemical staining and positron emission tomography (PET) imaging respectively. Plasma corticosterone measurements and forced swim tests were performed to evaluate the depressive performance. The staining results showed that repeated administration of MDMA increased expression of autophagosome and caused reduction in SERT densities of striatum and frontal cortex, which was ameliorated in the presence of 3-MA. PET imaging data also revealed that 3-MA could ameliorate MDMA-induced long-term decreased SERT availability in various brain regions of rats. Furthermore, immobility time of forced swim tests and plasma corticosterone levels were less in the group of MDMA co-injected with 3-MA compared with that of MDMA group. Together, these findings suggest that autophagy inhibition may confer protection against neurobiological and behavioral changes induced by MDMA. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Serotonin transporter (SERT) has been associated with many psychiatric diseases. This study investigated the biodistribution of a serotonin transporter imaging agent, N,N-dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM), in nonhuman primate brain using positron emission tomography (PET). Methods: Six and four Macaca cyclopis monkeys were used to determine the transit time (i.e., time necessary to reach biodistribution equilibrium) and the reproducibility of 4-[18F]-ADAM biodistribution in the brain, respectively. The sensitivity and specificity of 4-[18F]-ADAM binding to SERT were evaluated in one monkey challenged with different doses of fluoxetine and one monkey treated with 3,4-methylendioxymethamphetamine (MDMA). Dynamic PET imaging was performed for 3 h after 4-[18F]-ADAM intravenous bolus injection. The specific uptake ratios (SURs) in the midbrain (MB), thalamus (TH), striatum (ST) and frontal cortex (FC) were calculated. Results: The distribution of 4-[18F]-ADAM reached equilibrium 120–150 min after injection. The mean SURs were 2.49±0.13 in MB, 1.59±0.17 in TH, 1.35±0.06 in ST and 0.34±0.03 in FC, and the minimum variability was shown 120–150 min after 4-[18F]-ADAM injection. Using SURs and intraclass coefficient of correlation, the test/retest variability was under 8% and above 0.8, respectively, in SERT-rich areas. Challenge with fluoxetin (0.75–2 mg) dose-dependently inhibited the SURs in various brain regions. 4-[18F]-ADAM binding was markedly reduced in the brain of an MDMA-treated monkey compared to that in brains of normal controls. Conclusion: 4-[18F]-ADAM appears to be a highly selective radioligand for imaging SERT in monkey brain. [Copyright &y& Elsevier]

Abstract: An improved synthesis of N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, 2) as a potent serotonin transporter (SERT) imaging agent is described. Molecular orbital (MO) calculation predicts that N,N-dimethyl-2-(2-nitro-4-trimethylammoniumtrifluoromethanesulfonylphenylthio)benzamide (8) is probably a better precursor than N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) for preparing 2. Radioligand 2 was synthesized by the reaction of either precursor 1 or precursor 8 with K[18F]/K2.2.2 at 120°C followed by reduction with BH3 at 80°C. The radiochemical yield (EOB) of 2 synthesized from precursor 1 and 8 was 5.7±2.4% (n=6) and 14.8±4.0% (n=5), respectively, in a synthesis time of 120min from EOB. The specific activity of 2 was 3Ci/μmol or 111GBq/μmol (EOB). Thus, this new synthetic method has significantly improved the radiochemical yield of 4-[18F]-ADAM and makes this radioligand more accessible to PET Centers without a cyclotron. [Copyright &y& Elsevier]

Abstract: N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, 3) is a potent serotonin transporter (SERT) imaging agent. In order to fulfill the demand of pre-clinical studies, we have developed an automated synthesis unit to synthesize this radioligand. The 4-[18F]-ADAM was synthesized using TracerLab FN and FE modules and a modified module control program (TracerLab-Fx). The synthesis sequences were similar to that of the manual synthesis, i.e. nucleophilic fluorination of N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) with K[18F]/K2.2.2 followed by reduction with NaBH4/Cu(OAc)2 and purifications with high-performance liquid chromatography (HPLC) and solid phase extraction. The radiochemical yield of 3 was 1.5±0.3% (n=13, EOS). The synthesis time was 120min and the specific activity was 1.75±0.77Ci/μmol (n=13, EOS). The 4-[18F]-ADAM synthesized by this module was stable over 4h at room temperature and is suitable for imaging SERT in humans. [Copyright &y& Elsevier]