Specificity of Diastereomers of [99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents
Sanath K. MeegallaKarl PlößlMei‐Ping KungD. Andrew StevensonMuSteven A. KushnerLouise M. Liable‐SandsArnold L. RheingoldHank F. Kung
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Recently, we reported the first human study of [99mTc]TRODAT-1, technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3−)-oxo-[1R-(exo-exo)]-, as an imaging agent of central nervous system (CNS) dopamine transporters. Due to the existence of several chiral centers on this molecule, upon the formation of [99mTc]TRODAT-1 complex (2) several diastereomers could be created. Two major diastereomers of [99mTc]TRODAT-1 (2), designated as peak A (2A) and peak B (2B), were separated by HPLC. Biodistribution of the purified diastereomers 2A,B was evaluated in rats. It appears that 2A displayed a higher lipophilicity than 2B (PC = 305 and 229, respectively), and a similar trend was observed for the initial brain uptake at 2 min postinjection (0.50% and 0.28% dose/organ for 2A,B, respectively). At 60 min post-iv-injection, the specific uptakes, as measured by [striatum − cerebellum]/cerebellum ([ST−CB]/CB) ratio, were 1.72 and 2.79 for 2A,B, respectively. The higher [ST−CB]/CB ratio observed for 2B was corroborated by the results of an in vitro binding assay. Higher binding affinity for dopamine transporters was observed for 3B (Ki = 13.87 and 8.42 nM for the analogous rhenium complexes 3A,B, respectively). The structure of the [99mTc]TRODAT-1 complexes was deduced using nonradioactive rhenium as a surrogate for radioactive technetium complex. Reacting free TRODAT-1 ligand with [Bu4N][ReOCl4] yielded two major complexes: Re-TRODAT-1A (3A) and Re-TRODAT-1B (3B) (corresponding with peaks A and B of [99mTc]TRODAT-1, respectively), whose structures were determined by X-ray analysis. The X-ray structures show that both complexes have a pseudo-square-pyramidal structure of [RevO]3+N2S2 core with oxygen occupying the apical position and the N-alkyl substitution in syn-configuration to the oxo−rhenium bond. In conclusion, TRODAT-1 formed at least two diastereomers after complexing with a metal(V)−oxo (M = 99mTc, Re) center core. The two isomers display different binding affinities toward dopamine transporters and distinct properties of localization in the striatum area of the brain where the transporters are located.Keywords:
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Abstract We evaluated lipophilicity and biodistribution of a series of 99m Tc(CO) 3 ‐ether isonitrile complexes to determine whether different lipophilicity and structure of isonitrile ligands would improve the imaging properties of the radiopharmaceutical for the heart. Novel 99m Tc(CO) 3 ‐MIBI analogs were prepared and analyzed by radio‐HPLC, and their lipophilicity was determined. These new complexes could be bi‐ or tri‐substituted in specified pH conditions like 99m Tc(CO) 3 ‐MIBI. These new complexes exhibited low liver, lungs and blood uptake compared with [ 99m Tc(CO) 3 (MIBI) 3 ] + though their heart uptake was not so high. Among these complexes, [ 99m Tc(CO) 3 (EPI) 2 (OH 2 )] + showed higher target to non‐target ratios at 5 and 30 min post‐injection than that of [ 99m Tc(CO) 3 (MIBI) 3 ] + . Copyright © 2007 John Wiley & Sons, Ltd.
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The parameters of lipophilicity for three different groups of drugs (twelve analgesics drugs, eleven cardiovascular system drugs, and thirty six compounds characterized by divergent pharmacological activity) were experimentally determined by HPLC methods as well as calculated using various computer programs (HyperChem, ACD/Labs, ChemAxon, Dragon and VCCLab). The relationships between experimental (chromatographic) parameters of lipophilicity (log k and log kw) and the chemical structure of the studied compounds, and their comparison due to their lipophilic and hydrophilic character were presented. Moreover, the experimental and calculated values of parameters of lipophilicity were correlated and compared. Finally, both these groups of parameters of lipophilicity were analyzed using PCA or FA methods for the classification of studied compounds according to their chemical structures and pharmacological activity.
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This chapter contains sections titled: Chemical Nature of Lipophilicity Chemical Concepts Required to Understand the Significance of Lipophilicity Molecular Charges and Dipoles Intermolecular Forces Solvation and Hydrophobic Effect Lipophilicity Systems Determination of Log P and Log D Traditional Factorization of Lipophilicity (Only Valid for Neutral Species) General Factorization of Lipophilicity (Valid For All Species) Biological Relevance of Lipophilicity Lipophilicity and Membrane Permeation Lipophilicity and Receptor Affinity Lipophilicity and the Control of Undesired Human Ether-a-go-go-related Gene (hERG) Activity Conclusions
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The comparative molecular field analysis (CoMFA) method has been employed to correlate the apparent lipophilicity (logkw) and global lipophilicity (logP) for orthopramide derivatives. This study demonstrated that CoMFA is an excellent method in predicting the complex properties of molecules such as apparent lipophilicity (logkw) or lipophilicity (logP). The better predictability of lipophilicity by introducing logkw as an independent descriptor suggests that the HPLC capacity factor measured in a buffer of pH 7.5 (logkw) can be effectively utilized in the prediction of global lipophilicity.
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This chapter refers to tropane alkaloid compounds best known for their occurrence, biosynthesis, and pharmacological properties in a subsection of the plant family Solanaceae including the Atropa, Duboisia, Hyoscyamus, and Scopolia species, together with their semisynthetic derivatives. Tropane alkaloids are useful as parasympatholytics that competitively antagonize acetylcholine. The bicyclic ring of tropane moiety forms the base of these alkaloids, and the largest number of tropane alkaloids is substituted on the atom C-3 of the tropane ring in the form of ester derivatives. Also, this chapter provides routes to previous methods for synthesizing tropane-2-yl derivatives as well as new routes to synthesize 2-(p-toluenesulphonyl) tropane-2-ene (anhydroecgonine). The new strategy for synthesizing anhydroecgonine might be helpful to adopt the best method of synthesizing tropane-2-yl derivatives.
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Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction is to modulate the lipophilicity of the compound. In our group, we are interested in the study of the impact of fluorination on lipophilicity of aliphatic fluorohydrins and fluorinated carbohydrates. These are not UV-active, resulting in a challenging lipophilicity determination. Here, we present a straightforward method for the measurement of lipophilicity of fluorinated compounds by 19F NMR spectroscopy. This method requires no UV-activity. Accurate solute mass, solvent and aliquot volume are also not required to be measured. Using this method, we measured the lipophilicities of a large number of fluorinated alkanols and carbohydrates.
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Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction is to modulate the lipophilicity of the compound. In our group, we are interested in the study of the impact of fluorination on lipophilicity of aliphatic fluorohydrins and fluorinated carbohydrates. These are not UV-active, resulting in a challenging lipophilicity determination. Here, we present a straightforward method for the measurement of lipophilicity of fluorinated compounds by 19F NMR spectroscopy. This method requires no UV-activity. Accurate solute mass, solvent and aliquot volume are also not required to be measured. Using this method, we measured the lipophilicities of a large number of fluorinated alkanols and carbohydrates.
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