Macrocyclics Inc.

Dallas, TX, United States

Macrocyclics Inc.

Dallas, TX, United States
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Wu Y.,University of Texas at Dallas | Zhao P.,University of Texas at Dallas | Kiefer G.E.,University of Texas at Dallas | Kiefer G.E.,Macrocyclics Inc. | And 2 more authors.
Macromolecules | Year: 2010

A DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴- tetraacetic acid) tetraamide ligand having a single acrylamide side chain (M1) was copolymerized with either 2-methylacrylic acid (MAA), 2-(acryloylamino)-2- methyl-1-propanesulfonic acid (AMPS), or N-isopropylacrylamide (NIPAM) to create a series of linear random copolymers using classical free radical chain polymerization chemistry. The metal ion binding properties of hydrolyzed M1 were investigated by pH potentiometry and the europium(III) complexes of the resulting heteropolymers were evaluated as PARACEST imaging agents. All polymeric agents were found to possess similar intermediate-to-slow water exchange and CEST characteristics as the parent EuDOTA-tetraamide monomer. Consistent with basic multiplexing principles, the highest molecular weight polymer, Eu-DMAA 3.1, also showed the highest CEST sensitivity with a detection limit of 20 ± 2 μM. The second arylamide component gave polymers with widely different chemical characteristics and CEST properties. In particular, the Eu-DNIPAM 4.0 and Eu-DMAA 4.1 polymers displayed different solubility characteristics as a function of pH or temperature which, in turn, affected the water exchange and CEST properties of the corresponding agents. It was concluded that introduction of hydrophobic groups into the polymer backbone reduces solvent accessibility to the Eu3+ component, effectively slowing water exchange between the inner-sphere water coordination position at each Eu3+ center with bulk water. The CEST properties of the heteropolymers when dissolved in plasma suggest that the more hydrophobic characteristics of these polymers could be advantageous for in vivo applications. © 2010 American Chemical Society.


Yu J.,University of Texas at Dallas | Martins A.F.,University of Texas at Dallas | Preihs C.,University of Texas Southwestern Medical Center | Clavijo Jordan V.,University of Texas Southwestern Medical Center | And 8 more authors.
Journal of the American Chemical Society | Year: 2015

Given the known water exchange rate limitations of a previously reported Zn(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural targets were rationally designed to increase the rate of water exchange to improve MRI detection sensitivity. These new sensors exhibit fine-tuned water exchange properties and, depending on the individual structure, demonstrate significantly improved longitudinal relaxivities (r1). Two sensors in particular demonstrate optimized parameters and, therefore, show exceptionally high longitudinal relaxivities of about 50 mM-1 s-1 upon binding to Zn(II) and human serum albumin (HSA). This value demonstrates a 3-fold increase in r1 compared to that displayed by the original sensor, GdDOTA-diBPEN. In addition, this study provides important insights into the interplay between structural modifications, water exchange rate, and kinetic stability properties of the sensors. The new high relaxivity agents were used to successfully image Zn(II) release from the mouse pancreas in vivo during glucose stimulated insulin secretion. © 2015 American Chemical Society.


Evbuomwan O.M.,University of Texas at Dallas | Merritt M.E.,Southwestern Medical Center | Kiefer G.E.,University of Texas at Dallas | Kiefer G.E.,Macrocyclics Inc. | And 2 more authors.
Contrast Media and Molecular Imaging | Year: 2012

Silica nanoparticles of average diameter 53±3nm were prepared using standard water-in-oil microemulsion methods. After conversion of the surface Si-OH groups to amino groups for further conjugation, the PARACEST agent, EuDOTA-(gly)4 - was coupled to the amines via one or more side-chain carboxyl groups in an attempt to trap water molecules in the inner-sphere of the complex. Fluorescence and ICP analyses showed that ~1200 Eu3+ complexes were attached to each silica nanoparticle, leaving behind excess protonated amino groups. CEST spectra of the modified silica nanoparticles showed that attachment of the EuDOTA-(gly)4 - to the surface of the nanoparticles did not result in a decrease in water exchange kinetics as anticipated, but rather resulted in a complete elimination of the normal Eu3+-bound water exchange peak and broadening of the bulk water signal. This observation was traced to catalysis of proton exchange from the Eu3+-bound water molecule by excess positively charged amino groups on the surface of the nanoparticles. © 2012 John Wiley & Sons, Ltd.


Wu Y.,University of Texas at Dallas | Soesbe T.C.,University of Texas Southwestern Medical Center | Kiefer G.E.,University of Texas at Dallas | Kiefer G.E.,Macrocyclics Inc. | And 3 more authors.
Journal of the American Chemical Society | Year: 2010

A europium(III) DO3A-tris(amide) complex is reported for imaging pH by MRI using ratiometric chemical exchange saturation transfer (CEST) principles. Deprotonation of a single phenolic proton between pH 6 and 7.6 results in an ∼5 ppm shift in the water exchange CEST peak that is easily detected by MRI. Collection of two CEST images at two slightly different activation frequencies provides a direct readout of solution pH without the need of a concentration marker. © 2010 American Chemical Society.


Evbuomwan O.M.,University of Texas at Dallas | Kiefer G.,University of Texas at Dallas | Kiefer G.,Macrocyclics Inc. | Sherry A.D.,University of Texas at Dallas | Sherry A.D.,Advanced Imaging Research Center
European Journal of Inorganic Chemistry | Year: 2012

The synthesis and characterization of four new DOTA-tetraamide ligands having variable alkyl chain lengths (C 1, C 12, C 14, and C 16) and their respective europium(III) complexes are reported. The three EuL complexes having long alkyl chains spontaneously form micelles of variable size. The critical micelle concentration differed for each complex (lower for the C 16 complex than the C 12 complex) while micelle size increased with increasing alkyl chain length. Chemical exchange saturation transfer (CEST) experiments showed that all four Eu III complexes displayed slow-to-intermediate water exchange kinetics. As expected, the CEST signals in these complexes decreased with increasing temperatures due to faster water exchange but, interestingly, the CEST signals for the C 14 and C 16 complexes approached a maximum near 25 °C consistent with exchange limited CEST at or near room temperature. The water residence lifetimes obtained by fitting the CEST spectra to the Bloch equations increased in parallel with an increase in alkyl carbon chain-length. By comparisons with the monomethylamide complex, which served as control, the data illustrate that micelle formation serves to slow the rate of water exchange in these systems. The complex having the largest CEST effect per unit Eu III concentration (the C 16 analog) had a detection limit of 5.3 μM. This represents an approximate 250-fold increase in sensitivity relative to the monomethylamide control (detection limit â 1.3 mM). These features highlight the potential of using micelle-based systems such as these as paramagnetic chemical exchange saturation transfer (PARACEST) agents for molecular imaging by MRI. Four new EuDOTA-tetraamides with variable alkyl chains lengths were synthesized and their CEST properties were extensively studied. Three of these complexes werefound to spontaneously form micelles due to their long alkyl chains which resulted in a dramatic increase in their CEST sensitivities. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Song B.,University of Texas at Dallas | Song B.,Dalian University of Technology | Wu Y.,University of Texas Southwestern Medical Center | Yu M.,University of Texas at Dallas | And 6 more authors.
Dalton Transactions | Year: 2013

A europium(iii) DOTA-tetraamide complex was designed as a MRI sensor of singlet oxygen (1O2). The water soluble, thermodynamically stable complex reacts rapidly with 1O2 to form an endoperoxide derivative that results in an ∼3 ppm shift in the position of the Eu(iii)-bound water chemical exchange saturation transfer (CEST) peak. The potential of using this probe to detect accumulation of the endoperoxide derivative in biological media by ratiometric CEST imaging was demonstrated. © 2013 The Royal Society of Chemistry.


Ferreira C.L.,MDS Nordion | Yapp D.T.T.,British Columbia Cancer Agency Research Center | Yapp D.T.T.,University of British Columbia | Crisp S.,MDS Nordion | And 7 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2010

Purpose: Improved bifunctional chelates (BFCs) are needed to facilitate efficient 64Cu radiolabeling of monoclonal antibodies (mAbs) under mild conditions and to yield stable, target-specific agents. The utility of two novel BFCs, 1-Oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7, 10-triacetic acid (p-SCN-Bn-Oxo-DO3A) and 3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA), for mAb imaging with 64Cu were compared to the commonly used S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane- tetraacetic acid (p-SCN-Bn-DOTA). Methods: The BFCs were conjugated to trastuzumab, which targets the HER2/neu receptor. 64Cu radiolabeling of the conjugates was optimized. Receptor binding was analyzed using flow cytometry and radioassays. Finally, PET imaging and biodistribution studies were done in mice bearing either HER2/neu-positive or HER2/neu-negative tumors. Results: 64Cu-Oxo-DO3A- and PCTA-trastuzumab were prepared at room temperature in >95% radiochemical yield (RCY) in <30 min, compared to only 88% RCY after 2 h for the preparation of 64Cu-DOTA-trastuzumab under the same conditions. Cell studies confirmed that the immunoreactivity of the mAb was retained for each of the bioconjugates. In vivo studies showed that 64Cu-Oxo-DO3A- and PCTA-trastuzumab had higher uptake than the 64Cu-DOTA-trastuzumab at 24 h in HER2/neu-positive tumors, resulting in higher tumor to background ratios and better tumor images. By 40 h all three of the 64Cu-BFC-trastuzumab conjugates allowed for clear visualization of the HER2/neu-positive tumors but not the negative control tumor. Conclusion: The antibody conjugates of PCTA and Oxo-DO3A were shown to have superior 64Cu radiolabeling efficiency and stability compared to the analogous DOTA conjugate. In addition, 64Cu-PCTA and Oxo-DO3A antibody conjugates may facilitate earlier imaging with greater target to background ratios than the analogous 64Cu-DOTA antibody conjugates. © 2010 Springer-Verlag.


Jurek P.,Macrocyclics Inc. | Reibenspies J.H.,Texas A&M University | Kiefer G.E.,Macrocyclics Inc.
Acta Crystallographica Section C: Structural Chemistry | Year: 2016

1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) is of much interest in nuclear medicine for its ability to form copper complexes that are kinetically inert, which is beneficial in vivo to minimize the loss of radioactive copper. The structural chemistry of the hydrated HCl salt of CB-TE2A, namely 11-carboxymethyl-1,8-tetraaza-4,11-diazoniabicyclo[6.6.2]hexadecane-4-acetate chloride trihydrate, C16H31N4O4 + Cl- 3H2O, is described. The compound crystallized as a positively charged zwitterion with a chloride counter-ion. Two of the amine groups in the macrocyclic ring are protonated. Formally, a single negative charge is shared between two of the carboxylic acid groups, while one chloride ion balances the charge. Two intramolecular hydrogen bonds are observed between adjacent pairs of N atoms of the macrocycle. Two intramolecular hydrogen bonds are also observed between the protonated amine groups and the pendant carboxylate groups. A short intermolecular hydrogen bond is observed between two partially negatively charged O atoms on adjacent macrocycles. The result is a one-dimensional polymeric zigzag chain that propagates parallel to the crystallographic a direction. A second intermolecular interaction is a hydrogen-bonding network in the crystallographic b direction. The carbonyl group of one macrocycle is connected through the three water molecules of hydration to the carbonyl group of another macrocycle. © 2016 International Union of Crystallography.


PubMed | Texas A&M University and Macrocyclics Inc.
Type: Journal Article | Journal: Acta crystallographica. Section C, Structural chemistry | Year: 2016

1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) is of much interest in nuclear medicine for its ability to form copper complexes that are kinetically inert, which is beneficial in vivo to minimize the loss of radioactive copper. The structural chemistry of the hydrated HCl salt of CB-TE2A, namely 11-carboxymethyl-1,8-tetraaza-4,11-diazoniabicyclo[6.6.2]hexadecane-4-acetate chloride trihydrate, C16H31N4O4(+)Cl(-)3H2O, is described. The compound crystallized as a positively charged zwitterion with a chloride counter-ion. Two of the amine groups in the macrocyclic ring are protonated. Formally, a single negative charge is shared between two of the carboxylic acid groups, while one chloride ion balances the charge. Two intramolecular hydrogen bonds are observed between adjacent pairs of N atoms of the macrocycle. Two intramolecular hydrogen bonds are also observed between the protonated amine groups and the pendant carboxylate groups. A short intermolecular hydrogen bond is observed between two partially negatively charged O atoms on adjacent macrocycles. The result is a one-dimensional polymeric zigzag chain that propagates parallel to the crystallographic a direction. A second intermolecular interaction is a hydrogen-bonding network in the crystallographic b direction. The carbonyl group of one macrocycle is connected through the three water molecules of hydration to the carbonyl group of another macrocycle.


Perk L.R.,VU University Amsterdam | Vosjan M.J.W.D.,VU University Amsterdam | Visser G.W.M.,VU University Amsterdam | Budde M.,VU University Amsterdam | And 3 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2010

Purpose: Immuno-PET is an emerging imaging tool for the selection of high potential antibodies (mAbs) for imaging and therapy. The positron emitter zirconium-89 (89Zr) has attractive characteristics for immuno-PET with intact mAbs. Previously, we have described a multi-step procedure for stable coupling of 89Zr to mAbs via the bifunctional chelate (BFC) tetrafluorophenol-N-succinyldesferal (TFP-N-sucDf). To enable widespread use of 89Zr-immuno-PET, we now introduce the novel BFC p- isothiocyanatobenzyl-desferrioxamine B (Df-Bz-NCS) and compare its performance in 89Zr-immuno-PET with the reference BFC TFP-N-sucDf. Methods: Three mAbs were premodified with Df-Bz-NCS and labeled with 89Zr at different pHs to assess the reaction kinetics and robustness of the radiolabeling. Stability of both 89Zr-Df-Bz-NCS- and 89Zr-N-sucDf-conjugates was evaluated in different buffers and human serum. Comparative biodistribution and PET studies in tumor-bearing mice were undertaken. Results: The selected conjugation conditions resulted in a chelate:mAb substitution ratio of about 1.5:1. Under optimal radiolabeling conditions (pH between 6.8-7.2), the radiochemical yield was >85% after 60 min incubation at room temperature, resulting in radioimmunoconjugates with preserved integrity and immunoreactivity. The new radioimmunoconjugate was very stable in serum for up to 7 days at 37°C, with <5% 89Zr release, and was equally stable compared to the reference conjugate when stored in the appropriate buffer at 4°C. In biodistribution and imaging experiments, the novel and the reference radioimmunoconjugates showed high and similar accumulation in tumors in nude mice. Conclusions: The novel Df-Bz-NCS BFC allows efficient and easy preparation of optimally performing 89Zr-labeled mAbs, facilitating further exploration of 89Zr-immuno-PET as an imaging tool. © 2009 The Author(s).

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