High pressure assisted synthetic approach for novel 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline derivatives and their assessment as anticancer agents.

A novel, expedient and effective methodology for the synthesis of distinctly substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline systems has been developed with a new synthetic platform. This process includes ammonium acetate-mediated cyclocondensation reactions of 3-oxo-2-arylhydrazonopropanals with benzosuberone and tetralone precursors, respectively, using the high-pressure Q-tube reactor, which has been found to be superior to both conventional heating and microwave irradiation. The novel protocol benefits from its high atom efficiency, economy, ease of workup, broad substrate scope and is also applicable to gram-scale synthesis. To identify and confirm the newly synthesized targeted compounds, the X-ray single-crystal as well as all possible spectroscopic methods were utilized. The cytotoxicity of the newly synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j and 5,6-dihydrobenzo-[h]quinolines derivatives 6a-e were preliminary examined toward three cell lines of human cancer; lung cancer (A549), breast cancer (MCF-7) and colon cancer (HCT-116), by applying the MTT colorimetric assay. The achieved results reflected the promising profile of the prepared compounds in this study against cancer cells and have shown that members from the synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j exhibited promising cytotoxicity's against MCF-7, and A549 cancer cells respectively, while the HCT-116 (colon) cancer cells were inhibited by certain examples of 5,6-dihydrobenzo[h]quinoline derivatives 6c,d. These promising results could serve as a good primary base for further research into the design of anticancer drugs.

Synchrotron MicroCT Reveals the Potential of the Dual Contrast Technique for Quantitative Assessment of Human Articular Cartilage Composition.

Dual contrast micro computed tomography (CT) shows potential for detecting articular cartilage degeneration. However, the performance of conventional CT systems is limited by beam hardening, low image resolution (full-body CT), and long acquisition times (conventional microCT). Therefore, to reveal the full potential of the dual contrast technique for imaging cartilage composition we employ the technique using synchrotron microCT. We hypothesize that the above-mentioned limitations are overcome with synchrotron microCT utilizing monochromatic X-ray beam and fast image acquisition. Human osteochondral samples (n = 41, four cadavers) were immersed in a contrast agent solution containing two agents (cationic CA4+ and non-ionic gadoteridol) and imaged with synchrotron microCT at an early diffusion time point (2 h) and at diffusion equilibrium (72 h) using two monochromatic X-ray energies (32 and 34 keV). The dual contrast technique enabled simultaneous determination of CA4+ (i.e., proteoglycan content) and gadoteridol (i.e., water content) partitions within cartilage. Cartilage proteoglycan content and biomechanical properties correlated significantly (0.327 < r < 0.736, p < 0.05) with CA4+ partition in superficial and middle zones at both diffusion time points. Normalization of the CA4+ partition with gadoteridol partition within the cartilage significantly (p < 0.05) improved the detection sensitivity for human osteoarthritic cartilage proteoglycan content, biomechanical properties, and overall condition (Mankin, Osteoarthritis Research Society International, and International Cartilage Repair Society grading systems). The dual energy technique combined with the dual contrast agent enables assessment of human articular cartilage proteoglycan content and biomechanical properties based on CA4+ partition determined using synchrotron microCT. Additionally, the dual contrast technique is not limited by the beam hardening artifact of conventional CT systems. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:563-573, 2020.

Ruthenium-Based Catalytic Systems Incorporating a Labile Cyclooctadiene Ligand with N-Heterocyclic Carbene Precursors for the Atom-Economic Alcohol Amidation Using Amines.

Transition-metal-catalyzed amide-bond formation from alcohols and amines is an atom-economic and eco-friendly route. Herein, we identified a highly active in situ N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic system for this amide synthesis. Various substrates, including sterically hindered ones, could be directly transformed into the corresponding amides with the catalyst loading as low as 0.25 mol.%. In this system, we replaced the p-cymene ligand of the Ru source with a relatively labile cyclooctadiene (cod) ligand so as to more efficiently obtain the corresponding poly-carbene Ru species. Expectedly, the weaker cod ligand could be more easily substituted with multiple mono-NHC ligands. Further high-resolution mass spectrometry (HRMS) analyses revealed that two tetra-carbene complexes were probably generated from the in situ catalytic system.

Four selected high molecular weight heterocyclic aromatic hydrocarbons: Ecotoxicological hazard assessment, environmental relevance and regulatory needs under REACH.

Little is known about the ecotoxicity of heterocyclic aromatic hydrocarbons (NSO-HETs) to aquatic organisms. In the environment, NSO-HETs have been shown to occur in a strong association with their unsubstituted carbocyclic analogues, the polycyclic aromatic hydrocarbons (PAH), for which much more information is available. The present study addressed this issue by investigating the toxicity of four selected NSO-HETs in green algae (Desmodesmus subspicatus), daphnids (Daphnia magna) and fish embryos (Danio rerio). The four high molecular weight NSO-HETs dibenz[a,j]acridine (DBA), 7H-dibenzo[c,g]carbazole (DBC), benzo[b]naphtho[2,1-d]thiophene (BNT) and benzo[b]naphtho[1,2-d]furan (BNF) were selected, based on the results of a previous research project, indicating a lack of toxicity data and a high potential for persistence and bioaccumulation. The solubilities of the NSO-HETs in the test media were determined and turned out to be comparatively low (2.7-317 µg/L) increasing in the following order: DBA < BNT « DBC « BNF. Exposure concentrations during the toxicity tests were quantified with GC-MS and decreased strongly possibly due to sorption or metabolising during the test periods (48-96 h). Therefore, the estimated effect concentrations were related to the mean measured concentrations, as endpoints related to nominal concentrations would have underestimated the toxicity many times over. Within the range of the substance solubilities, BNF affected all test organisms with fish embryos being the most sensitive (fish: EC50 6.7 µg/L, algae: EC10 17.8 µg/L, daphnids: EC50 55.8 µg/L). DBC affected daphnids (EC50 2.5 µg/L,) and algae (EC10 3.1 µg/L), but not fish embryos. The lowest toxicity endpoint was observed for BNT affecting only algae (NOEC 0.556 µg/L) and neither daphnids nor fish embryos. DBA did not show any effects on the tested organisms in the range of the water solubility. However, we would expect effects in long-term toxicity studies to fish and aquatic invertebrates for all substances at lower concentrations, which needs further investigation. All four NSO-HETs were identified in mussels (Mytilus edulis) from the German coasts, in green kale (Brassica oleracea var. acephala) and in freshwater harbor sediment in concentrations between 0.07 and 2 µg/kg, highlighting their relevance as environmental contaminants. There is a need to regulate the four NSO-HETs within the REACH regulation due to their intrinsic properties and their environmental relevance. However, acquisition of additional experimental data appears to be pivotal for a regulation under REACH.

Synthesis and toxicity assessment of 3-oxobutanamides against human lymphocytes and isolated mitochondria.

To reduce costly late-phase compound scrubbing, there has been an increased focus on assessing compounds within in vitro assays that predict properties of human safety liabilities, before preclinical in vivo studies. The aim of our study was to answer the questions that whether the toxicity risk of a series of 3-oxobutanamide derivatives could be predicted by using of human lymphocytes and their isolated mitochondria. Using biochemical and flow cytometry assessments, we demonstrated that exposure of lymphocytes and isolated mitochondria to five 3-oxobutanamide derivatives (1-5) did not exhibit remarkable toxicity at low concentrations (50-500µM) but toxicity could be observed at high concentrations (1000 and 2000µM), particularly for N-(5-(4-bromophenyl)-3-isoxazolyl)-3-oxobutanamide (4) and N-(2-benzothiazolyl)-3-oxo butanamide (5). Compounds 4, 5 and partly N-(5-methyl-3-isoxazol yl)-3-oxo butanamide (1) also showed a marked cellular and mitochondrial toxicity while compound 5 displayed superior toxicity. Compound 5 induced cytotoxicity on human blood lymphocytes which was associated with the generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation and depletion of glutathione. Our results suggested that among assessed compounds, increased toxicity of compound 5 compared to other compounds could be likely attributed to the presence of bromine substituent in 5. Finally our findings proposed that using of antioxidants and mitochondrial/lysosomal protective agents could be beneficial in decreasing the toxicity of 5.

Assessment of H2S in vivo using the newly developed mitochondria-targeted mass spectrometry probe MitoA.

Hydrogen sulfide (H2S) is produced endogenously in vivo and has multiple effects on signaling pathways and cell function. Mitochondria can be both an H2S source and sink, and many of the biological effects of H2S relate to its interactions with mitochondria. However, the significance of mitochondrial H2S is uncertain, in part due to the difficulty of assessing changes in its concentration in vivo Although a number of fluorescent H2S probes have been developed these are best suited to cells in culture and cannot be used in vivo To address this unmet need we have developed a mitochondria-targeted H2S probe, MitoA, which can be used to assess relative changes in mitochondrial H2S levels in vivo MitoA comprises a lipophilic triphenylphosphonium (TPP) cation coupled to an aryl azide. The TPP cation leads to the accumulation of MitoA inside mitochondria within tissues in vivo There, the aryl azido group reacts with H2S to form an aryl amine (MitoN). The extent of conversion of MitoA to MitoN thus gives an indication of the levels of mitochondrial H2S in vivo Both compounds can be detected sensitively by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the tissues, and quantified relative to deuterated internal standards. Here we describe the synthesis and characterization of MitoA and show that it can be used to assess changes in mitochondrial H2S levels in vivo As a proof of principle we used MitoA to show that H2S levels increase in vivo during myocardial ischemia.

Human whole blood 1 H2 O transverse relaxation with gadolinium-based contrast reagents: Magnetic susceptibility and transmembrane water exchange.

PURPOSE: To characterize transverse relaxation in oxygenated whole blood with extracellular gadolinium-based contrast reagents by experiment and simulation. METHODS: Experimental measurements of transverse 1 H2 O relaxation from oxygenated whole human blood and plasma were made at 1.5 and 3.0 Tesla. Spin-echo refocused and free-induction decays are reported for blood and plasma samples containing four different contrast reagents (gadobenate, gadoteridol, gadofosveset, and gadobutrol), each present at concentrations ranging from 1 to 18 mM (i.e., mmol (contrast reagent (CR))/L (blood)). Monte Carlo simulations were conducted to ascertain the molecular mechanisms underlying relaxation. These consisted of random walks of water molecules in a large ensemble of randomly oriented erythrocytes. Bulk magnetic susceptibility (BMS) differences between the extra- and intracellular compartments were taken into account. All key parameters for these simulations were taken from independent published measurements: they include no adjustable variables. RESULTS: Transverse relaxation is much more rapid in whole blood than in plasma, and the large majority of this dephasing is reversible by spin echo. Agreement between the experimental data and simulated results is remarkably good. CONCLUSION: Extracellular field inhomogeneities alone make very small contributions, whereas the orientation-dependent BMS intracellular resonance frequencies lead to the majority of transverse dephasing. Equilibrium exchange of water molecules between the intra- and extracellular compartments plays a significant role in transverse dephasing. Magn Reson Med 77:2015-2027, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Use of Phthalimidoacetyl Isothiocyanate as a Scaffold in the Synthesis of Target Heterocyclic Systems, and Their Antimicrobial Assessment.

Phthalimidoacetyl isothiocyanate underwent addition-cyclization reactions with some nitrogen and carbon nucleophilic reagents. Simultaneous or subsequent cyclization of the obtained adducts gave target heterocyclic systems such as 1,2,4-triazoles, 1,3-diazines, 1,3-oxazines and thiourea attached to a phthalimido moiety. The antimicrobial activity of the synthesized compounds was tested.

Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99-411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99-411 significantly decreased the systemic exposure of piperaquine by half-fold while it had no effect on the kinetics of lumefantrine. 99-411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99-411, an in situ permeability study was performed by co-perfusing lumefantrine and 99-411. In presence of lumefantrine, the absorption of 99-411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99-411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99-411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well.

The AHA Moment: Assessment of the Redox Stability of Ionic Liquids Based on Aromatic Heterocyclic Anions (AHAs) for Nuclear Separations and Electric Energy Storage.

Because of their extended conjugated bond network, aromatic compounds generally have higher redox stability than less saturated compounds. We conjectured that ionic liquids (ILs) consisting of aromatic heterocyclic anions (AHAs) may exhibit improved radiation and electrochemical stability. Such properties are important in applications of these ILs as diluents in radionuclide separations and electrolytes in the electric energy storage devices. In this study, we systematically examine the redox chemistry of the AHAs. Three classes of these anions have been studied: (i) simple 5-atom ring AHAs, such as the pyrazolide and triazolides, (ii) AHAs containing an adjacent benzene ring, and (iii) AHAs containing electron-withdrawing groups that were introduced to reduce their basicity and interaction with metal ions. It is shown that fragmentation in the reduced and oxidized states of these AHAs does not generally occur, and the two main products, respectively, are the H atom adduct and the imidyl radical. The latter species occurs either as an N σ-radical or as an N π-radical, depending on the length of the N-N bond, and the state that is stabilized in the solid matrix is frequently different from that having the lowest energy in the gas phase. In some instances, the formation of the sandwich π-stack dimer radical anions has been observed. For trifluoromethylated anions, H adduct formation did not occur; instead, there was facile loss of fluoride from their fluorinated groups. The latter can be problematic in nuclear separations, but beneficial in batteries. Overall, our study suggests that AHA-based ILs are viable candidates for use as radiation-exposed diluents and electrolytes.

Synthesis, relaxation properties and in vivo assessment of a carborane-GdDOTA-monoamide conjugate as an MRI blood pool contrast agent.

The synthesis, relaxivity measurements and in vivo assessment of a carborane-GdDOTA-monoamide (CB-GdDOTA-MA) amphiphilic conjugate as a blood pool contrast agent (BPCA) is reported. This BPCA exhibited excellent binding (87.4%) with human serum albumin (HSA) and showed a higher relaxivity value (r1 = 6.8 mM(-1) s(-1), 7 T) as compared to the clinically used BPCA, MS-325 (r1 = 5.1 mM(-1) s(-1), 9.4 T) in PBS. The blood pool contrast enhancement (CE) capability of CB-GdDOTA-MA was evaluated by performing MR angiography (MRA) in CF1 mice (n = 4) at a Gd dose of 0.1 mmol per kg body weight. The significant CE of blood vessels persisted for about 3-4 min post-injection (p.i.) and quickly diminishes over time. The significant CE of the bladder for up to 3 h p.i. indicated that the renal system is the primary clearance pathway for CB-GdDOTA-MA. However, the CE of liver tissues and intestine (up to 24 h p.i.) is suggestive of a significant hepatic uptake of the CB-GdDOTA-MA.

Gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2] 1,3-dipolar cycloaddtion cascade reaction: an efficient strategy for syntheses of medium-sized-ring ethers and amines.

A highly efficient strategy for the formation of medium-sized-ring ethers and amines based on a gold-catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium-sized-ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium-sized ring synthesis.

A step-economical route to fused 1,2,3-triazoles via an intramolecular 1,3-dipolar cycloaddition between a nitrile and an in situ generated aryldiazomethane.

An intramolecular 1,3-dipolar cycloaddition strategy for rapid entry into triazole-fused heterocyclic compounds without recourse to the traditional Cu(1)-catalyzed azide-alkyne cycloadditions is described. Central to the strategy is the in situ generation of substituted diazomethanes in a two-step sequence from the corresponding aldehydes, which then undergo smooth cycloaddition with a cyano group to generate the desired fused 1,2,3-triazoles in good overall yields. The entire sequence can be carried out in a one-pot operation.

Cobalt- and iron-catalyzed redox condensation of o-substituted nitrobenzenes with alkylamines: a step- and redox-economical synthesis of diazaheterocycles.

A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.

Three methods for 18F labeling of the HER2-binding affibody molecule Z(HER2:2891) including preclinical assessment.

UNLABELLED: Human epidermal growth factor receptor (HER2)-targeted Affibody molecules radiolabeled with (18)F allow the noninvasive assessment of HER2 status in vivo through PET imaging. Such agents have the potential to improve patient management by selecting individuals for HER2-targeted therapies and allowing therapy monitoring. The aim of this study was to assess different (18)F radiolabeling strategies of the HER2-specific Affibody molecule Z(HER2:2891), preclinically determine the biologic efficacy of the different radiolabel molecules, and select a preferred radiolabeling strategy to progress for automated manufacture. METHODS: Cysteine was added to the C terminus of the Affibody molecule for the coupling of maleimide linkers, and 3 radiolabeling strategies were assessed: silicon-fluoride acceptor approach ((18)F-SiFA), (18)F-AlF-NOTA, and 4-(18)F-fluorobenzaldehyde ((18)F-FBA). The biodistributions of the radiolabeled Affibody molecules were then determined in naïve CD-1 nude mice, and tumor targeting was assessed in CD-1 nude mice bearing high-HER2-expressing NCI-N87 tumors and low-HER2-expressing A431 tumors. The (111)In-ABY-025 compound, which has demonstrable clinical utility, served as a reference tracer. RESULTS: The non-decay-corrected radiochemical yields based on starting (18)F-fluoride using the (18)F-FBA, (18)F-SiFA, and (18)F-AlF-NOTA methods were 13% ± 3% (n = 5), 38% ± 2% (n = 3), and 11% ± 4% (n = 6), respectively. In naïve mice, both the (18)F-AlF-NOTA-Z(HER2:2891) and the (111)In-ABY-025 compounds showed a significant kidney retention (70.3 ± 1.3 and 73.8 ± 3.0 percentage injected dose [%ID], respectively, at 90 min after injection), which was not observed for (18)F-FBA-Z(HER2:2891) or (18)F-SiFA-Z(HER2:2891) (4.8 ± 0.6 and 10.1 ± 0.7 %ID, respectively, at 90 min). The (18)F-SiFA-Z(HER2:2891) conjugate was compromised by increasing bone retention over time (5.3 ± 1.0 %ID/g at 90 min after injection), indicating defluorination. All the radiolabeled Affibody molecules assessed showed significantly higher retention in NCI-N87 tumors than A431 tumors at all time points (P < 0.05), and PET/CT imaging of (18)F-FBA-Z(HER2:2891) in a dual NCI-N87/A431 xenograft model demonstrated high tumor-to-background contrast for NCI-N87 tumors. CONCLUSION: The HER2 Affibody molecule Z(HER2:2891) has been site-selectively radiolabeled by three (18)F conjugation methods. Preliminary biologic data have identified (18)F-FBA-Z(HER2:2891) (also known as GE226) as a favored candidate for further development and radiochemistry automation.

Bile acid-based 1,2,4-trioxanes: synthesis and antimalarial assessment.

A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg×4 days. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg×4 days and 24 mg/kg×4 days, respectively.

Multicomponent and sequential organocatalytic reactions: diversity with atom-economy and enantiocontrol.

Reactions in which several components are combined in sequence, and without isolation of intermediates, are greatly sought because of the inherent molecular diversity, efficiency, and atom-economy. However, organocatalytic reactions, employing an organic catalyst to assemble products of high enantiomeric excess (a single optical isomer), are also cutting-edge methodology. This tutorial review covers the overlap of these two areas, outling the structural diversity and stereocontrol arising from one-pot combinations of at least three components, powerful approaches with great potential that minimise formation of by-products and operating costs.

Stability assessment of different chelating moieties used for elemental labeling of bio-molecules.

Integrating elemental labeling in quantitative LC-ICP-MS based bio-analysis requires fundamental experiments concerning the stability of complexes during analysis. In a competitive approach complex stability of the chelating moieties 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraaceticacid (DOTA), 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) and diethylenetriaminepentaacetic dianhydride (DTPA) in combination with 11 different lanthanides was investigated under typical chromatographic conditions. Measurements were carried out via LC-ICP-QMS using a novel mixed mode separation method. The influence of chromatographic separation, pH and temperature on complex stability constants was assessed regarding further applications of multiplexing in bio-analytical assays. The limit of detection (LOD) for LC-ICP-QMS was 0.03 nM for all investigated Tm complexes (0.15 fmol absolute). Quantification of the complexes was performed via external, flow injection based calibration. For all investigated complexes the stability was significantly decreased by the chromatographic conditions. Moreover, complexation by DOTA revealed two different signals suggesting the presence of a stable intermediate product. Ln(3+)-DOTA and Ln(3+)-NOTA complexes provided high stability at 5 °C and 37 °C over a time of 12 hours, whereas Ln(3+)-DTPA complexes showed significant degradation at 37 °C.

Assessment of neovascular permeability in a pancreatic tumor model using dynamic contrast-enhanced (DCE) MRI with contrast agents of different molecular weights.

OBJECT: We evaluated the relationship of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters and contrast agents with different molecular weights (MW) in a pancreatic tumor mouse model. MATERIALS AND METHODS: Panc02 tumors were induced in mice at the hind leg. DCE-MRI was performed using Gadolinium (Gd)-based contrast agents with different MW: Gd-DOTA (0.5 kDa), P846 (3.5 kDa), and P792 (6.47 kDa). Quantitative vascular parameters (AUC, K(trans), V(e), and V(p)) were calculated according to a modified Tofts two-compartment model. Values for all contrast groups were compared for tumor and control (muscle) tissues. RESULTS: Values for K(trans) and V(e) were significantly higher in tumor tissue than in muscle tissue. When comparing contrast agents, lowest absolute K(trans) values were observed using P792. The relative increase in K(trans) in tumor tissue compared with normal tissue was highest after the use of P792. In both tumor and normal tissues, K(trans) decreased with increasing molecular weight of the contrast agent used. CONCLUSION: It was demonstrated that values for the different DCE-MRI vascular (permeability) parameters are highly dependent on the contrast agent used. Due to their potential to better differentiate tumor from muscle tissue, higher molecular weight contrast agents show promise when evaluating tumors using DCE-MRI.

Preparation, characterization and in vivo assessment of Gd-albumin and Gd-dendrimer conjugates as intravascular contrast-enhancing agents for MRI.

We report in vivo and in vitro MRI properties of six gadolinium-dendrimer and gadolinium-albumin conjugates of derivatized acyclic diethylenetriamine-N,N',N',N″, N″-pentaacetic acid (1B4M) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (C-DOTA). The three albumin-based agents have comparable protein to chelate ratios (1:16-18) as well as molar relaxivity (8.8-10.4 mM(-1) s(-1)). The three dendrimer based agents have blood clearance half-lives ranging from 17 to 66 min while that of the three albumin-based agents are comparable to one another (40-47 min). The dynamic image obtained from use of the albumin conjugate based on the macrocycle (C-DOTA) showed a higher contrast compared to the remaining two albumin based agents. Our conclusion from all of the results is that the macrocyclic-based (DOTA) agents are more suitable than the acyclic-based (1B4M) agent for in vivo use based on their MRI properties combined with the kinetic inertness property associated with the more stable Gd(III) DOTA complex.