Boronic acid adducts of technetium dioxime (BATO) complexes derived from quinuclidine benzilate (QNB) boronic acid stereoisomers: Syntheses and studies of their binding to the muscarinic acetylcholine receptor

Jurisson, Silvia S.; Pirro, John P.; DiRocco, Richard J.; Rosenspire, Karen C.; Jagoda, Elaine M.; Nanjappan, P.; Eckelman, William C.; Nowotnik, David P.; Nunn, Adrian D.

doi:10.1016/0969-8051(94)00125-4

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…Several recent reports demonstrate that it is possible to incorporate a [Tc v O] 3+ N 2 S 2 or [Tc v O] 3+ NS 3 core into potential receptor-selective imaging agents for muscarinic receptors, , vesamicol sites, serotonin receptors, − dopamine D1 and D2 receptors, ,, and steroid hormone receptors. − Use of boronic acid adducts of technetium dioxime (BATO type of complexes) as muscarinic receptor imaging agents has been reported . However, these Tc-99m imaging agents have demonstrated limited success in in vivo studies …”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22][23][24][25][26][27] Use of boronic acid adducts of technetium dioxime (BATO type of complexes) as muscarinic receptor imaging agents has been reported. 28 However, these Tc-99m imaging agents have demonstrated limited success in in vivo studies. 27 There are various factors that may contribute to the failure of Tc-99m receptor imaging agents.…”

Section: Introductionmentioning

confidence: 99%

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Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

et al. 1998

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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-)-o xo- [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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

et al. 1998

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“…It is well established that when [ 99m Tc]pertechnetate (TcO 4 - ), the most commonly available starting material, is reduced by a reducing agent, such as stannous chloride, in the presence of “soft” chelating ligands, including N 2 S 2 and NS 3 , [Tc v O] 3+ N 2 S 2 or [Tc v O] 3+ NS 3 complexes are formed. Several recent reports demonstrate that it is possible to incorporate [Tc v O] 3+ N 2 S 2 into potential receptor-selective imaging agents for muscarinic receptors, vesamicol sites, and steroid hormone receptors. − The use of other chelating agents for preparing Tc-99m muscarinic receptor-imaging agents has also been reported . However, all of these central nervous system (CNS) receptor-specific Tc-99m imaging agents have demonstrated limited success in in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

“…[25][26][27][28][29][30] The use of other chelating agents for preparing Tc-99m muscarinic receptor-imaging agents has also been reported. 31 However, all of these central nervous system (CNS) receptor-specific Tc-99m imaging agents have demonstrated limited success in in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Technetium-99m-Labeled Tropanes as Dopamine Transporter-Imaging Agents

Plößl

et al. 1997

J. Med. Chem.

138

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In the development of novel Tc-99m-labeled tropane derivatives as dopamine transporter (reuptake site)-imaging agents, a series of neutral and lipophilic complexes containing bis-(aminoethanethiol) as a neutral complexing moiety for a [99mTc]TcO3+ center core was successfully prepared. Biological evaluation of the Tc-99m-labeled complexes 13-16 as central nervous system (CNS) dopamine transporter-imaging agents was reported. Synthesis of the tropane derivatives was achieved by stepwise reactions adding two aminoethanethiol units. The final free thiol ligands were obtained by deblocking the 4-methoxybenzyl protecting group with Hg(OAc)2 to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of 16, displayed good initial brain uptake and selective uptake in the striatal area, where dopamine transporters are concentrated. One of the compounds, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethy] amino]ethanethiolato-(3-)-N2,N2',S2,S2'] oxo-[1R-(exo-exo)]- [99mTc]technetium,[99mTc]TRODAT-1 (13), displayed the highest initial uptake in rat brain (0.4% at 2 min post iv injection); the striatal/cerebellar (ST/ CB) ratio reached 2.8 at 60 min after an iv injection. The specific uptake in rat brain can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; iv, 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.2. In contrast, the specific striatal uptake was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). After an iv injection of 9 mCi of [99mTc]TRODAT-1 (13), in vivo images of baboon brain using single-photon emission-computed tomography exhibited excellent localization in striatum (basal ganglia), where dopamine neurons are known to be concentrated. This series of compounds may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS diseases (i.e., Parkinson's disease) in which changes in the dopamine transporter concentration are implicated.

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“…The potential of developing Tc-99m-labeled agents for receptor imaging is well recognized (4,15). Several recent papers demonstrated that it is possible to incorporate [ 99m Tc v O] 3+ N 2 S 2 [bis(aminoethanethiol) (BAT)] into potential receptor-selective imaging agents for muscarinic receptors (16), vesamicol sites (17), and steroid hormone receptors (18)(19)(20)(21)(22)(23).…”

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confidence: 99%

Tc-99m-Labeled Tropanes as Dopamine Transporter Imaging Agents

et al. 1996

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The development of novel Tc-9m-labeled tropane derivatives as dopamine transporter imaging agents is reported. A series of neutral and lipophilic conjugated complexes, containing N-(alkylthiolato)-tropane, aminobis(ethylthiolato), and a [99mTc]TcO3+ center core, were prepared and evaluated as central nervous system (CNS) dopamine transporter imaging agents in rats. One of the compounds, [99mTC]technetium, [methyl 3-(4-chlorophenyl)-8-(2-mercaptoethyl-8-azabicyclo [3.2.1]octane-2-carboxylato-S][[2,2'-(methylimino)bis[eth anethiolato]] (2-)-N,S,S']oxo (25), displayed low initial uptake in rat brain (0.1% at 2 min post i.v. injection); the striatal/cerebellar (ST/CB) ratio reached 3.50 at 60 min after an i.v. injection. The specific uptake can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, N-methyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; i.v. 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.0. In contrast, the specific uptake in striatum was not affected by pretreating rats with a noncompeting ligand, haldol (i.v., 1 mg/kg). In vitro autoradiography of rat brain sections exhibited elevated labeling in striatum, major islands of Calleja, and olfactory tubercle regions, where dopamine neurons are known to be concentrated. This series of compounds is the first example of technetium-99m labeled CNS receptor-specific imaging agents and may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS abnormality in conjunction with single photon emission computed tomography.

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Boronic acid adducts of technetium dioxime (BATO) complexes derived from quinuclidine benzilate (QNB) boronic acid stereoisomers: Syntheses and studies of their binding to the muscarinic acetylcholine receptor

Cited by 10 publications

References 34 publications

Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

Synthesis and Characterization of Technetium-99m-Labeled Tropanes as Dopamine Transporter-Imaging Agents

Tc-99m-Labeled Tropanes as Dopamine Transporter Imaging Agents

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Boronic acid adducts of technetium dioxime (BATO) complexes derived from quinuclidine benzilate (QNB) boronic acid stereoisomers: Syntheses and studies of their binding to the muscarinic acetylcholine receptor

Cited by 10 publications

References 34 publications

Specificity of Diastereomers of [99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

Specificity of Diastereomers of [99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

Synthesis and Characterization of Technetium-99m-Labeled Tropanes as Dopamine Transporter-Imaging Agents

Tc-99m-Labeled Tropanes as Dopamine Transporter Imaging Agents

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Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents

Specificity of Diastereomers of [^99mTc]TRODAT-1 as Dopamine Transporter Imaging Agents