Insights into the development of 99mTc-radioligands for serotonergic receptors imaging: Synthesis, labeling, In vitro, and In vivo studies.

Serotonergic (5-hydroxytryptamine; 5-HT) receptors play critical roles in neurological and psychological disorders such as schizophrenia, anxiety, depression, and Alzheimer's diseases. Therefore, it is particularly important to develop novel radioligands or modify the existing ones to identify the serotonergic receptors involved in psychiatric disorders. Among the 16 subtypes of serotonergic systems, only technetium-99m based radiopharmaceuticals have been evaluated for serotonin-1A (5-HT1A), serotonin-2A (5-HT2A), 5-HT1A/7 heterodimers and serotonin receptor neurotransmitter (SERT). This review focuses on recent efforts in the design, synthesis and evaluation of 99mTc-radioligands used for single photon emission computerized tomography (SPECT) imaging of serotonergic (5-HT) receptors. Additionally, the discussion will cover aspects such as chemical structure, in vitro/vivo stability, affinity toward serotonin receptors, blood-brain barrier permeation (BBB), and biodistribution study.

Synthetic approaches and structural diversity of triazolylbutanols derived from voriconazole in the antifungal drug development.

Voriconazole (VCZ) was the first approved triazole antifungal drug with 1-(1H-1,2,4-triazol-1-yl)butan-2-ol substructure. This drug showed a broad spectrum of activity, especially against yeasts and molds, and opened a new avenue toward the novel class of systemic antifungal agents. Modification of 2-fluoropyrimidine in the side chain of VCZ resulted in a newer generation of triazolylbutanols including efinaconazole, albaconazole, ravuconazole, and isavuconazole with the favorable antifungal spectrum, enhanced pharmacokinetic properties, and tolerable toxicity profiles. Due to the importance of triazolylbutanols in the discovery and development of new antifungal agents, in this review we have focused on the synthetic approaches and structural diversity of triazolylbutanols derived from voriconazole. This comprehensive review provides highlighting scope for medicinal chemists for the design, synthesis and development of novel potential antifungal drugs having better activity, pharmacokinetic property and toxicity profile.

Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging.

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT7Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers 99mTc-PHH and 99mTc-MPHH were synthesized in high radiochemical purity (>95%). 99mTc-MPHH showed a higher affinity to 5-HT7Rs on U-87 MG cells compared to 99mTc-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to 99mTc-MPHH, the 99mTc-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of 99mTc-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT7 receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of 99mTc-PHH and 99mTc-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

Current advances of triazole alcohols derived from fluconazole: Design, in vitro and in silico studies.

Currently, the available antifungal agents have significant clinical incompetency in terms of their clinical efficacy, antifungal spectrum, unfavorable pharmacokinetic profiles, substantial side effects and drug-drug interactions. Thus, the optimization and improvement of existing drugs and identification of new antifungal agents are urgently needed. Fluconazole is the first triazole alcohol drug with good in vivo efficacy against yeasts and well-known targets in fungal cells. However, the wide use of fluconazole as a first-line antifungal therapy has led to the development of resistance in clinical isolates of Candida species including Candida albicans and the emerging non-albicans Candida spp. In the last years, extensive efforts inflected to design and discovery of triazole alcohols derived from fluconazole by replacing one triazole ring with the proper side chain. In this paper, we have reviewed the structural modification of fluconazole to pursuit potent triazole alcohols with improved anti-Candida activity, and have highlighted their in vitro activities and in silico studies.

Synthesis and characterization of novel polymer-drug conjugates based on the poly(styrene-alt-maleic anhydride) as a potential method for drug release.

Six well known drugs, captopril, metformin-HCl, metroniazole, nortriptyline-HCl, fluoxetine-HCl and betahistin-HCl, were grafted to poly(styrene-alt-maleic anhydride) (PSMA). Grafting was attained by combining of anhydride groups in the PSMA with therapeutic agents containing NH, OH or SH groups. The covalently grafted drugs were identified by infrared, (1)H NMR and UV-Vis spectroscopy. The drug release data at different times fits well to the Korsmeyer-Peppas equation. The analysis of the exponent n of this model revealed a dominant Fickian diffusion mechanism under the in vitro conditions. Furthermore, mean dissolution time values (45.9 to 86.7 h) indicate a high resistance against drugs transport, the highest being obtained for betahistin-HCL.