Determination of Synthetic Impurities and Metabolic Products of F-ADAM, a Positron Emission Tomography Imaging Agent for Serotonin Transporter (SERT) Using HPLC-Tandem Mass Spectrometry

A high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analytical method was developed to determine the identity of impurities resulting from the synthesis of N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzyl-amine (F-ADAM), as well as its metabolic products by rat liver microsomes. 18F-ADAM is an important positive electron emission ligand commonly employed as a radio-imaging agent for serotonin transporter (SERT) in the brain. F-ADAM and its derivatives were separated using HPLC on a C4-phenyl column with an ammonium formate aqueous buffer/acetonitrile programmed mobile phase. Synthetic contaminants and metabolic products were identified using fragmentation spectra obtained by tandem mass spectrometry. We show that F-ADAM is unstable in methanol, and propose the use of acetonitrile to generate optimal chromatogram. A Cl-substituted species was found to be the major impurity resulting from the F-ADAM synthetic process. The metabolic products of F-ADAM by rat liver microsomes were characterized by oxidization of the sulfur moiety to sulfoxide, demethylation of the dimethylamine moiety, and oxidative defluorination/deamination. These results elucidate the by-products of F-ADAM synthetic and metabolic processes, and provide direction for the application of this imaging agent to biosystems properly.

Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone Deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPLC-MS/MS

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

Determination of Impurities and Degradation Products/Causes for <i>m</i>-Iodobenzylguanidine Using HPLC-Tandem Mass Spectrometry

m-Iodobenzylguanidinium hemisulfate (MIBGHS) is a precursor in the preparation of radioiodine-labeled m-iodobenzylguanidine (MIBG), which is used as a radio-imaging and therapy agent for neuroendocrine tumors and myocardial sympathetic nerve function. To ensure the quality and efficacy of the medicine and prevent side effects, the precursor purity, source of impurity, and derivatives have to be determined. In this study, the purity of synthesized MIBGHS and the amount of contaminants therein were determined by high-performance liquid chromatography and ultraviolet detection, gradient eluted by ammonium formate aqueous solution and acetonitrile mobile phase on both C8 and phenyl type column. The impurities were identified on the basis of molecular and fragmented ion mass spectra using of electrospray ionization triple quadrupole tandem mass spectrometry. The results revealed the presence of process-related impurities including m-bromobenzylguanidine (MBrBG) and overreacted byproducts. Stress test results indicated that MIBGHS is stable under acidic and dry thermal conditions for at least 72 h but MIBG aqueous solution was deteriorated slowly when exposed to UV light, thermal, oxidative and alkaline environments. Thus, m-iodobenzylamine, the starting material intended for the synthesis of MIBGHS should be analyzed to ensure that it is free from m-bromobenzylamine impurity. Stored under normal condition (-18°C), MIBGHS is stable for at least 12 months. The chemically labile guanidine and amine groups in MIBGHS are the major causes of its instability, while iodide loss from the phenyl group is a minor cause.

Sexual Behavior, Function and Satisfaction in Headache Associated with Sexual Activity: A Systematic Review of Literature

Introduction: Headache associated with sexual activity (HSA) is the painful event of head and neck precipitated only by sexual activity. The negative impact of sexuality is expected to be more severe in HSA patients and their partners than other headache disorder. In addition, social and cultural taboo may conceal sexual problem or hinder seeking counseling for sexual perplexity. A sufficient scientific evidence is therefore needed to clarify the misunderstanding and schedule appropriate education in clinical practice. Methods: A systematic review of literature was completed to elucidate the sexual behavior, function and satisfaction in HSA patients and their partners. Results: A total of 97 publications are eligible after careful screening. However, most of the studies focus on the etiopathogenesis or treatment. Sexual change was mentioned in 23 publications. Orgasmic headache is the most frequent type of HSA. The HSA occurs more frequent in dyadic than extradyadic sexual activity. Intercourse is the leading sexual act for HSA occurrence, following by masturbation. A few patients suffer HSA under specific sexual position, like kneeling, and trigger, such as cannabis. Pain can be rapidly ceased in half of patients when sexual activity was halted. Sexual function and sexual satisfaction may decrease in HSA patient and partner but improve after pain reversal. Conclusions: A shortage of sexuality data of HSA is documented in literature but that still clarifies the extradyadic and masturbatory effect on HSA occurrence. Nevertheless, HSA disturbs sexual function and satisfaction in patients and their partners. The pathogenesis of pain includes two components, the hypersympathetic status and exertional action. Therefore, physician can schedule their education and counseling for HSA according to these findings. Further investigation for sexual function and satisfaction is warranted.

Current Evidence of the Monoaminergic Regulation of Romantic Love and Relationship

Introduction: Sexual response cycle is modulated by a variety of biological factors, especially antidepressants and antipsychotics. Although the circuit of romantic love has recently been delineated, the biological impact on romantic love is barely mentioned in human, however. Methods: In thus study, a comprehensive literature review was completed to elucidate the role of central monoamines, including dopamine, serotonin, norepinephrine, epinephrine, melatonin and histamine, for the romantic love and relationship in human. Results: The central circuit of romantic love includes the mesolimbic and mesocortical tract and their extensions widely distributed in cortical, subcortical and brainstem structures. The activation of brain foci progressively decreases along with the romantic relationship in many areas, including the bilateral caudate and ventral tegmentum area without change of passionate love. Hyperactivity of dopamine and serotonin is suggested at the synaptic level for romantic love in lovers, probably through an inhibition of transporters or increase of terminal release. Romantic love can be modulated by antidepressants or recreational drugs. Polymorphism of dopamine and serotonin receptor relates to the romantic relationship. The effect of other monoamines is barely mentioned. Conclusions: Romantic love is vulnerable for secondary effect, such as drugs which modulate the dopamine and serotonin, in human. Romantic relationship is also impacted by the polymorphism of monoamine receptors. Therefore, the biological effect is not limited to sexual response cycle but also the romantic love and relationship. Further investigation is warranted for understanding the secondary effect in romantic love for romantic dissolution or divorce.