The Relationship Between Relative Hydration Free Energies of 99mTcON2S2 Complexes and Their Brain Uptakes

A thermodynamic integration dual-transform method was firstly applied to calculating the relative hydration free energies of ^99mTcON2S2 complexes. The relationship between the brain uptakes(B, U. ) of ^99mTcON2S2 complexes with different substituted functional groups and their relative hydration free energies was investigated. The simulation results show that the experiment brain uptake(B. U. ) data are strongly influenced by the relative hydration free energies of ^99mTcON2S2 complexes, thus the simulations can provide the useful information for the medicine design of ^99mTc brain imaging agents.     

Characterization of technetium-99m complexes of pentane-2,4-dione bis(N-methylthiosemicarbazone)

Further characterization of the two neutral technetium-99m (99mTc) complexes of pentane-2,4-dione bis-(N-methylthiosemicarbazone) (PETS) was carried out using a new dianionic PETS derivative, 3,3-dimethyl-pentane-2,4-dione bis(N-methylthiosemicarbazone) (DM-PETS), and the well characterized 99mTc complex of 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (DADT) as references. While PETS generated two neutral 99mTc complexes, 99mTc-PETS-L1 and 99mTc-PETS-L2, by both the stannous reduction method and the ligand exchange reaction with six-coordinated 99mTc(V) complex of N,N'-ethylenebis(acetylacetone imine), DM-PETS formed only one neutral 99mTc complex. 99mTc-PETS-L2, the more lipophilic complex of the two 99mTc-PETS, was obtained with a much higher yield than 99mTc-PETS-L1 by the ligand exchange reaction of PETS with the five-coordinated 99mTc(V) complex of glucoheptonate. In addition, while 99mTc-PETS-L2 and 99mTc-DADT remained unchanged in the presence of CN- anions, a breakdown of the original complexes was observed in 99mTc-PETS-L1 and 99mTc-DM-PETS. All four 99mTc complexes exhibited similar brain, heart and pancreas extraction when injected into mice. These cumulative results imply that 99mTc-PETS-L1 and 99mTc-DM-PETS are six-coordinated mononuclear 99mTc(V) complexes and that 99mTc-PETS-L2 is a five-coordinated mononuclear 99mTc(V) complex. These results also suggest that while the chelate ring structure of the 99mTc-dithiosemicarbazone (DTS) chelate played a significant role in its stability, ionization of the third proton of the PETS molecule and the subsequent resonating structure afforded further stability to the 99mTc-PETS complex. Markedly high lipophilicity of the 99mTc-PETS-L2 may also be explained by assuming that 99mTc-PETS-L2 is the five-coordinated resonating structure.     

Synthesis and biological evaluation of a novel 99mTc‐cyclopentadienyltricarbonyl technetium complex as a new potential brain perfusion imaging agent

A new cytectrene prototype of general formula RCpTc(CO)₃ (R = C₆H₅NHCO, Cp = cyclopentadienyl moiety) has been synthesized from N‐phenylferrocenecarboxamide 2 , characterized and evaluated as a potential brain perfusion imaging agent. An improved procedure has been developed to obtain both the ligand 2 , characterized by its solid‐state structure (orthorhombic, Pccn, a = 10.4443(2) Å, b = 26.1467(6) Å, c = 9.9977(3) Å), and the corresponding metallic Tc‐ and Re‐complexes in good yield. These latter complexes possessed similar HPLC retention times, thereby indicating identity of their molecular structures. The Tc‐complex ^99m Tc‐2 is lipophilic enough to cross the blood‐brain barrier. This complex exhibits good brain uptake (1.41% injected dose per gram tissue at 5 min) combined with a fairly good retention of radioactivity in brain (0.48% injected dose per gram tissue after 1 h). Then, the distribution of the activity at 5 min post‐injection in various rat brain regions showed a higher accumulation in the hippocampus area. The new ^99mTc‐cyclopentadienyltricarbonyl technetium complex reported here showed promising biological results, making it an interesting base for the development of a new generation of cytectrene as brain perfusion imaging agent. Copyright © 2011 John Wiley & Sons, Ltd.     

Preliminary studies of 99mTc-PQQ-NMDAR binding and effect of specificity binding by mannitol

Pyrroloquinoline quinone (PQQ) is a powerful neuroprotectant that specifically binds to brain NMDA receptors and inhibits excitotoxicity. Imaging this binding reaction in the brain remains a long sought goal in this field of study, and one of the primary challenges remaining is enabling soluble labeled PQQ to pass the blood–brain barrier (BBB). Previously, our group successfully labeled PQQ with Technetium-99m (^99mTc), a metastable nuclear isomer used in radioactive isotope medical tests. In this work, we determined the specific binding of ^99mTc-PQQ and NMDAR by radioligand receptor assay. Ebselen (EB) and MK-801 both effectively inhibited ^99mTc-PQQ binding. We then investigated methods of opening the BBB using mannitol to enable entry to the brain by ^99mTc-PQQ. Our results showed that 7.5 mL/kg of 20 % mannitol effectively opened the BBB and 20 min was the optimum treatment time. Competition studies showed that mannitol did not affect the specific binding between ^99mTc-PQQ and NMDA receptors. Using this method, the amount of ^99mTc-PQQ uptake and retention was increased most significantly in the hippocampus and cortex, and re-opening the BBB did not affect binding. Together, our results demonstrate that the use of mannitol to open the BBB may contribute significantly to improving image quality by increasing the uptake amount of a water-soluble agent in brain.     

Novel tetradentate diamine dioxime ligands: synthesis,characterization and in vivo behavior of their 99mTc‐complexes

Two novel diamine dioxime ligands, 4,7‐diaza‐3,8‐diethyldecane‐2,9‐dione bis oxime (3) and 4,9‐diaza‐3,10‐diethyldodecane‐2,11‐dione bis oxime (5), were synthesized in order to develop new brain perfusion imaging agents, based on ^99mTc(V)‐complexes. The synthesis involved condensation of 2‐hydroxyimino‐3‐pentanone with appropriate diamine in protic solvent which afforded the bis imine adducts. Subsequent reduction of imine functional groups yielded a diastereoisomeric mixture of 3 and 5. UV–visible, IR, ¹H NMR, ¹³C NMR and elemental analysis were used to characterize the structures of the synthesized compounds. ^99mTc‐complexes of both diamine dioximes were prepared and radiolabeling conditions optimized to give the maximum yield. Physicochemical parameters of the labeled complexes as well as and their biodistribution in rats were investigated. Both compounds (3 and 5) formed ^99mTc‐complexes with a net charge of zero, determined by electrophoresis. The resultant lipophilic ^99mTc‐complexes of 3 and 5 were readily formed at pH ~9.0 within 10 min at room temperature with yields of 90% and 95%, respectively. The ^99mTc‐3 complex was found to be stable within 1 h, while ^99mTc‐5 was stable for a few hours. A significant brain uptake of ^99mTc‐3 (2.1% injected dose) and ^99mTc‐5 (1.8% injected dose) complexes, 2 min after injection, is in accordance with their lipophilicity. The present study suggests that both ligands are promising candidates as new ^99mTc‐based brain‐imaging agents. Copyright © 2012 John Wiley & Sons, Ltd.     

meta-Substituted benzamide oligomers that complex mono-, di- and tricarboxylates: folding-induced selectivity and chirality

meta-Substituted arylamide trimer, pentamer and heptamer have been prepared from simple benzene-1,3-diamine, benzene-1,3-dicarboxylic acid, and 3-aminobenzoic acid units. 2D NOESY (1)H NMR experiments reveal that these flexible oligomers form folded conformations to complex di- and tricarboxylate anions of varying sizes and shapes in DMSO of high polarity, which is driven by multiple intermolecular N-H···O=C and C-H···O=C hydrogen-bonds between the amide and aromatic hydrogens of the oligomers and the carboxylate oxygens of the anions. Generally, tricarboxylate anions display an increased binding affinity compared with the dicarboxylate anions and the complexes formed by 1,3-benzenedicarboxylate anion are more stable than those formed by 1,2- or 1,4-benzenedicarboxylate anions. Circular dichroism experiments show that chiral glutamic acid dianion can induce the oligomers to produce chiral bias, leading to the formation of chiral supramolecular complexes.     

99mTc标记COI配合物的制备及其用作心室显像剂的初步研究

通过改变异腈配体的结构和配合物的中心核,以期获得标记方法简单、放化纯度高以及生物性能优良的新型心室显像剂.以环辛胺为原料,通过甲酰胺化和脱水两步反应制得配体环辛基异腈(COI),并以氯化亚锡为还原剂和二硫代肼基甲酸甲酯为供氮体,通过配体交换反应得到放化纯度大于95%的^99mTcN-COI标记物.以氯化亚锡为还原剂直接标记制得放化纯度大于95%的^99mTc-COI配合物.两种标记物在室温下放置6h以上,其放化纯度无明显变化.在正常昆明小鼠体内进行的生物分布实验研究结果显示,^99mTcN-COI和^99mTc-COI在心脑中有一定摄取,但肝、肺及血等本底摄取相对较高.二者在血液中都有很高的浓集,且滞留也很好,其中^99mTc-COI配合物在静脉注射后60min时的血/心、血/肝和血/肺摄取比分别为6.67,1.54和2.07,有望成为一种新型的制备方法简单的心室显像剂.     

Synthesis of several MPP derivatives for ~(99m)Tc-labelling and evaluated as potential 5-HT_(1A) receptor imaging agents

The(2-methoxyphenyl) piperazine(MPP) was selected as the functional group and conjugated to dithiocarbamate through different spacers.A series of new MPP derivatives(MPPnDTC,n = 2-6) were synthesized and radiolabelled with 99mTc-nitrido core or 99mTc-tricarboxyl core as potential 5-HT1A receptor imaging agents.All the six 99mTc-labelled complexes were lipophilic and neutral.Biodistribution results showed that those radiotracers had moderate initial brain and hippocampus uptake.There have no significant rela...     

Synthesis and biodistribution of two novel 99mTc “3+1”mixed ligand complexes as potential brain perfusion agents

The research in the last decade has been mainly aimed at the development of technetium-99m radiopharmaceuticals, among which are the “3+1”mixed ligand complexes. Two novel [^99mTc]“3+1”mixed ligand complexes each carrying the tridentate ligand, the N-(o-Methylthiophenyl)ethylenediamine or the N-(o-Methylthiophenyl)-b-mercaptoacetamide in combination with monothiolate coligand were produced using stannous chloride as reductant and glucoheptonate as transfer ligand. The identification of [^99mTc]-6 and [^99mTc]-7 was established by thin layer chromatography. The radiochemical purity of two complexes was over 90%. Biodistribution data in mice showed that both [^99mTc]-6 and [^99mTc]-7 can penetrate the intact blood-brain barrier and exhibited retention in mice brain. The brain uptakes (%ID/g) were 1.76, 1.17, 0.90 and 0.68, 0.38 ,0.37 at 2, 30, and 60 minutes i.v. postinjection for [^99mTc]-6 and [^99mTc]-7, respectively. Examples in this report comfirm us that it is promising to develop ^99mTc complexes as potential brain perfusion agents based on modifying either the tridentate or the monodentate ligands. This revised version was published online in August 2006 with corrections to the Cover Date.     

一种新型脑灌注显像剂99mTcN-CPDTC的制备及生物分布

目前临床上广泛使用的99mTc脑灌注显像剂是以［99mTcO］3+核为中心核的配合物99mTc-乙撑双半胱氨酸二乙酯(99mTc-ECD)和99mTc-六甲基丙撑二胺肟(99mTc-HMPAO). ［99mTc≡N］2+核由于具有较高的化学稳定性以及用99mTcN核代替99mTcO核后其配合物的生物分布性能发生了较大的改变［1～3］, 因此研究含99mTcN核的配合物成为寻找新型放射性药物的一条有效途径.     

Technetium-99m nitride radiopharmaceuticals

Following the introduction of an efficient method for the preparation of technetium-99m complexes containing a terminal Tc-N multiple bond, under conditions suitable for nuclear medicine applications, new radiopharmaceuticals for heart and brain imaging have been discovered. These compounds belong to the class of bi-substituted, square-pyramidal nitride TcV complexes with dithiocarbamate ligands, and are the first examples of radiopharmaceuticals of this type exhibiting interesting biological properties. The peculiar chemical characteristics of the Tc-N core can also be conveniently utilized for the design of radiopharmaceuticals incorporating bioactive peptides and having definite structural features.     

New BATO complexes for brain and myocardial imaging

Two new BATO complexes^99mTcC1 (dmg)₃BC₆H₄CH₃ (Cholor[bis {2,3-butanedionedioxime(1-)-O} {2,3-butanedionedioximato (2-)-N,N',N",N'",N",N"'} (m-tolueneborato) technetium]) and^99m TcCl (4-MCDO)₃MeB, ([bis{4-methyl-1,2-cyclohexanedioximato (1-)-O} {4-methyl-cyclohexane-1, 2-dione-dioximato (2-)-O} {methyl-borato (2-)-N,N', N", N'", N", N"'} chlorotechnetium]), generally called BATO (Boronic Acid Adducts of Technetium Dioximes, had been synthesized and evaluated for potential use in brain and myocardial perfusion imaging. Their labeling conditions were also investigated. In their biodistribution studyies they showed higher radiochemical stability and rapid brain uptake and myocardial uptake in mice. After i.v administration, the first complex had 0.87%ID in the brain and 1.02% ID in the heart at 2 min and it had a longer retention in brain (0.62%ID was maintained at 15 min postinection) but rapidly cleared from heart (0.33%ID postinjection). For the second complex, it showed very rapid blood clearance. The uptake of heart, lung and blood in mice at 2 min respectively were: 1.32%ID, 2.48%ID and 6.66%ID. These two complexes formation were 2rapid, simple and of high yield(91%). The processes were easy to kit formulation.     

Production, quality control and pharmacokinetic studies of 177Lu–zoledronate for bone pain palliation therapy

A new dipeptide derivative, ethyl 2-(3-(4-hydroxyphenyl)-2-(2-(4-phenyl-5-((pyridin-4-ylamino)methyl)-4H-1,2,4-triazol-3-ylthio)acetamido)propanamido)-3-(1H-indol-3-yl)propanoate (EHPTIP) was successfully synthesized and radiolabeled with ¹²⁵I by the direct electrophilic substitution method. The non radiolabeled compound (EHPTIP) was tested as an antimicrobial agent and the radiolabeled derivative was tested as a new imaging agent. The study results showed a good antimicrobial activity of EHPTIP and a good in vitro and in vivo stability of ¹²⁵I-EHPTIP. The biodistribution of the radiolabeled compound showed a high brain uptake of 7.60 ± 0.01 injected activity/g tissue organ at 30 min post-injection and retention in brain remained high up to 1 h, whereas the clearance from the normal mice appeared to proceed via the renal system. Such brain uptake is better than that of currently used radiopharmaceuticals for brain imaging (^99mTc-ECD and ^99mTc-HMPAO). As a conclusion, EHPTIP is a newly synthesized dipeptide with a good antimicrobial activity and the radioiodinated EHPTIP which is labeled with ¹²³I could be used as a novel agent for brain SPECT.     

<Superscript>99m</Superscript>Tc-labelled biguanide derivatives: chemical speciation modelling thereof and evaluation in vervets

^99mTc-DMSA (dimercaptosuccinic acid) is known to be a safe and effective agent for static renal imaging. However, it has a long uptake time which is a limiting factor in diagnostic procedures and also leads to a relatively high radiation dose being administered to patients. There is a constant search for possible new renal imaging agents with a good resolution, kidney/liver contrast and low radiation dose to all organs. A series of biguanide derivatives (potential as non-insulin-dependent diabetes mellitus agents) labelled with ^99mTc were investigated as potential alternative kidney-imaging agents on theoretical grounds (in silico) and their biodistribution (in vivo) verified in a limited number of animal experiments. Such a dual approach has the benefit that it reduces the number of animal experiments needed to evaluate a potential radiopharmaceutical. The blood plasma model shows little or no complexation of the biguanide type ligands by the metal ions in blood plasma. It was therefore expected that these ligands will clear rapidly through the kidneys and liver (increased lipophilicity). These predictions were verified by studies on single vervets comparing them with ^99mTc-DMSA as gold standard. All the biguanide derivatives labelled with ^99mTc show liver, kidney and gallbladder uptake in vervets. It was shown that the agent ^99mTc-CBIG (carboxylbiguanide) has a very fast kidney clearance, which will reduce the dose to organs (as experienced for ^99mTc-DMSA), although it’s potential as a kidney agent is limited by its gallbladder uptake.     

Discrete and infinite 1D, 2D/3D cage frameworks with inclusion of anionic species and anion-exchange reactions of Ag3L2 type receptor with tetrahedral and octahedral anions

Complexes [PF6 subset(Ag3(titmb)2](PF6)2 (8) and {SbF6 subset[Ag3(titmb)2](SbF6)2}.H2O.1.5 CH3OH (9) are obtained by reaction of titmb and Ag+ salts with different anions (PF6(-) and SbF6(-)), and crystal structures reveal that they are both M3L2 cage complexes with short Ag...F interactions between the silver atoms and the fluorine atoms of the anions. In complex 8, a novel cage dimer is formed by weak Ag...F contacts; an unique cage tetramer formed via Ag...pi interactions (Ag...eta5-imidazole) between dimers and an infinite 1D cage chain is presented. However, each of the external non-disordered SbF6(-) anions connect with six cage 9s via Ag...F contacts, and each cage 9 in turn connects with three SbF6(-) anions to form a 2D network cage layer; and the layers are connected by pi-pi interactions to form a 3D network. The anion-exchange reactions of four Ag3L2 type complexes ([BF4 subset(Ag3(titmb)2](BF4)2 (6), [ClO4 subset(Ag3(titmb)2](ClO4)2 (7b), [PF6 subset(Ag3(titmb)2](PF6)2 (8) and [SbF6 subset(Ag3(titmb)2](SbF6)2.1.5CH3OH (9)) with tetrahedral and octahedral anions (ClO4(-), BF4(-), PF6(-) and SbF6(-)) are also reported. The anion-exchange experiments demonstrate that the anion selective order is SbF6(-) > PF6(-) > BF4(-), ClO4(-), and this anion receptor is preferred to trap octahedral and tetrahedral anions rather than linear or triangle anions; SbF6(-) is the biggest and most preferable one, so far. The dimensions of cage complexes with or without internal anions, anion-exchange reactions, cage assembly and anion inclusions, silver(I) coordination environments, Ag-F and Ag-pi interactions of Ag3L2 complexes 1-9 are discussed.     

三唑烯醇手性识别的分子力学研究

近十几年来 ,解决不同类型手性化合物的分离是手性色谱发展的前沿领域 [1～ 3] ,对手性识别机理的研究也逐渐引起重视 [4 ,5] ,但由于缺乏手性固定相和手性化合物分子复合体的单晶数据 ,有关手性分离机理的通用定量解释方法很不完善 .采用分子模型设计和理论计算方法 ,研究 CSPs与手性化合物复合体的三维结构性质 ,不仅易于获得 CSPs与 R-体、S-体之间能量的差值 ,而且能直观地得出手性识别发生的位置、作用力的性质及其大小 ,这对于新型 CSPs的设计 ,药物动力学研究和药物分子设计具有十分重要的意义 .本文利用分子力学方法研究了手性…     

Anion Effects on Sodium Ion and Acid Molecule Adduction to Protein Ions in Electrospray Ionization Mass Spectrometry

Gaseous protein–metal ion and protein–molecule complexes can be readily formed by electrospray ionization (ESI) from aqueous solutions containing proteins and millimolar concentrations of sodium salts of various anions. The extent of sodium and acid molecule adduction to multiply charged protein ions is inversely related and depends strongly on the proton affinity (PA) of the anion, with extensive sodium adduction occurring for anions with PA values greater than ~300 kcal·mol^–1 and extensive acid molecule adduction occurring for anions with PA values less than 315 kcal·mol^–1. The role of the anion on the extent of sodium and acid molecule adduction does not directly follow the Hofmeister series, suggesting that direct protein–ion interactions may not play a significant role in the observed effect of anions on protein structure in solution. These results indicate that salts with anions that have low PA values may be useful solution-phase additives to minimize nonspecific metal ion adduction in ESI experiments designed to identify specific protein-metal ion interactions.     

MO tripeptide diastereomers (M=99/99mTc, Re): models to identify the structure of 99mTc peptide targeted radiopharmaceuticals

Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO complexes. Upon complexation with [TcO]3+, two products form; these are syn and anti diastereomers, and they often have different biological behavior. This is the case with the approved radiopharmaceutical [99mTcO]depreotide ([99mTcO]P829, NeoTect) that is used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higher organ uptake and slower blood clearance than the anti compounds.     

Chromatographic characterization of electrochemically generated technetium-HEDP skeletal imaging agents

Reduction of pertechnetate [(99m)TcO(-)(4)] by controlled-potential coulometry in the presence of 1-hydroxy-1,1-ethanediphosphonate (HEDP) leads to the formation of (99m) Tc complexes which are suitable for bone imaging. The complex radiopharmaceutical mixtures can be separated into their respective components by anion-exchange high-performance liquid chromatography. The distribution of the complexes in the mixtures is dependent on the cell potential, pH, technetium concentration, and presence or absence of air. A single component formed in high yield and isolated from the mixture by HPLC was investigated as a potential bone-imaging agent. This particular complex is produced only in low yields when prepared by chemical reduction of (99m) TcO(-)(4). Thus electrochemistry shows promise in aiding in the development of a more efficacious bone-imaging agent by allowing selective generation of individual (99m) Tc-HEDP complexes.     

Phenol Based‐Ligands with Two Adjacent N,N′,O‐Binding Pockets

The synthesis of three new ligands and their coordination behavior towards zinc ions with strongly coordinating anions and cobalt ions with weakly coordinating anions are reported. The ligands have two adjacent imidazolyl‐pyridinyl and pyrazolyl‐pyridinyl binding pockets, respectively, which are linked by a phenol unit. We also investigated the dynamic behavior of the ligand having the imidazolyl‐pyridiyl sidearm in solution. The reaction of the ligands and ZnCl₂ yielded complexes of the type [ L Zn₂Cl₃]. When we used Co^II salts with weakly coordinating anions, complexes of the general formula [ L ₂Co₂]²⁺ were formed.