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    Imaging tumor vasculature noninvasively with positron emission tomography and RGD peptides labeled with copper 64 using the bifunctonal chelates DOTA, oxo-DO3a. and PCTA. Yapp Donald T T,Ferreira Cara L,Gill Rajanvir K,Boros Eszter,Wong May Q,Mandel Derek,Jurek Paul,Kiefer Garry E Molecular imaging Two novel bifunctional chelates, 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) and 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (Oxo-DO3A), were found to radiolabel antibodies with copper 64 (64Cu) well for positron emission tomography (PET). In this study, the same chelators were used to radiolabel peptides with 64Cu for PET imaging of angiogenesis. PCTA, Oxo-DO3A, and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) were conjugated to cyclic-(RGDyK), and their binding affinities were confirmed. Conditions for 64Cu radiolabeling were optimized for maximum yield and specific activity. The in vitro stability of the radiolabeled compounds was challenged with serum incubation. PET studies were carried out in a non-αvβ3-expressing tumor model to evaluate the compounds' specificity for proliferating tumor vasculature and their in vivo pharmacokinetics. The PCTA and Oxo-DO3A bioconjugates were labeled with 64Cu at higher effective specific activity and radiochemical yield than the DOTA bioconjugate. In the imaging studies, all the 64Cu bioconjugates could be used to visualize the tumor and the radiotracer uptake was blocked with cyclic-(RGDyK). Target uptake of each bioconjugate was similar, but differences in other tissues were observed. 64Cu-PCTA-RGD showed the best clearance from nontarget tissue and the highest tumor to nontarget ratios. PCTA was the most promising bifunctional chelate for 64Cu peptide imaging and warrants further investigation.
    Gd(DOTAlaP): exploring the boundaries of fast water exchange in gadolinium-based magnetic resonance imaging contrast agents. Boros Eszter,Karimi Shima,Kenton Nathaniel,Helm Lothar,Caravan Peter Inorganic chemistry Here, we describe the synthesis of the single amino acid chelator DOTAlaP and four of its derivatives. The corresponding gadolinium(III) complexes were investigated for their kinetic inertness, relaxometric properties at a range of fields and temperatures, water exchange rate, and interaction with human serum albumin (HSA). Derivatives with one inner-sphere water (q = 1) were determined to have a mean water residency time between 8 and 6 ns in phoshate-buffered saline at 37 °C. The corresponding europium complexes were also formed and used to obtain information on the hydration number of the corresponding coordination complexes. Two complexes capable of binding HSA were also synthesized, of which one, Gd(5b), contains no inner-sphere water, while the other derivative, Gd(4b), is a mixture of ca. 15% q =1 and 85% q = 0. In the presence of HSA, the latter displayed a very short mean water residency time (τM(310) = 2.4 ns) and enhanced relaxivity at intermediate and high fields. The kinetic inertness of Gd(4b) with respect to complex dissociation was decreased compared to its DOTAla analogue but still 100-fold more inert than [Gd(BOPTA)(H2O)](2-). Magnetic resonance imaging in mice showed that Gd(4b) was able to provide 38% better vessel to muscle contrast compared to the clinically used HSA binding agent MS-325. 10.1021/ic5008928
    RGD conjugates of the H2dedpa scaffold: synthesis, labeling and imaging with 68Ga. Boros Eszter,Ferreira Cara L,Yapp Donald T T,Gill Rajanvir K,Price Eric W,Adam Michael J,Orvig Chris Nuclear medicine and biology INTRODUCTION:The rekindled interest in the (68)Ga generator as an attractive positron emission tomography generator system has led us and others to investigate novel chelate systems for (68)Ga. We have previously reported our findings with the acyclic, rapidly coordinating chelate H(2)dedpa and its model derivatives. METHODS:In this report, we describe the synthesis of the corresponding bifunctional chelate scaffolds (H(2)dp-bb-NCS and H(2)dp-N-NCS) as well as the radiolabeling properties, transferrin stability, binding to the target using in vitro cell models and in vivo behavior the corresponding conjugates with the α(v)β(3) targeting cyclic pentapeptide cRGDyK (monomeric H(2)RGD-1 and dimeric H(2)RGD-2). RESULTS:The ability of the conjugated ligands to coordinate Ga isotopes within 10 min at room temperature at concentrations of 1 nmol was confirmed. Complex [(67)Ga(RGD-1)](+) was more stable (92% after 2 h) than [(67)Ga(RGD-2)](+) (73% after 2 h) in a transferrin challenge experiment. IC(50) values for both conjugates (H(2)RGD-1 and H(2)RGD-2) and nonconjugated RGD were determined in a cell-based competitive binding assay with (125)I-echistatin using U87MG cells, where enhanced specific binding was observed for the multivalent H(2)RGD-2 conjugate compared to the monovalent H(2)RGD-1 and nonconjugated cRGDyK. The U87MG cell line was also used to generate subcutaneous xenograft tumors on RAG2M mice, which were used to evaluate the in vivo properties of [(68)Ga(RGD-1)](+) and [(68)Ga(RGD-2)](+). After 2 h of dynamic imaging, both block and nonblock mice were sacrificed to collect select organs at the 2-h time point. Although the uptake is specific, as judged from the ratios of nonblock to block (2.36 with [(67)Ga(RGD-1)](+), 1.46 with [(67)Ga(RGD-2)](+)), both conjugates display high uptake in blood. CONCLUSIONS:We have successfully synthesized and applied the first bifunctional versions of H(2)dedpa for conjugation to a targeting vector and subsequent imaging of the corresponding conjugates. 10.1016/j.nucmedbio.2012.01.003
    (68)Ga small peptide imaging: comparison of NOTA and PCTA. Ferreira Cara L,Yapp Donald T T,Mandel Derek,Gill Rajanvir K,Boros Eszter,Wong May Q,Jurek Paul,Kiefer Garry E Bioconjugate chemistry In this study, a bifunctional version of the chelate PCTA was compared to the analogous NOTA derivative for peptide conjugation, (68)Ga radiolabeling, and small peptide imaging. Both p-SCN-Bn-PCTA and p-SCN-Bn-NOTA were conjugated to cyclo-RGDyK. The resulting conjugates, PCTA-RGD and NOTA-RGD, retained their affinity for the peptide target, the α(v)β(3) receptor. Both PCTA-RGD and NOTA-RGD could be radiolabeled with (68)Ga in >95% radiochemical yield (RCY) at room temperature within 5 min. For PCTA-RGD, higher effective specific activities, up to 55 MBq/nmol, could be achieved in 95% RCY with gentle heating at 40 °C. The (68)Ga-radiolabeled conjugates were >90% stable in serum and in the presence of excess apo-transferrin over 4 h; (68)Ga-PCTA-RGD did have slightly lower stability than (68)Ga-NOTA-RGD, 93 ± 2% compared to 98 ± 1%, at the 4 h time point. Finally, the tumor and nontarget organ uptake and clearance of (68)Ga-radiolabeled PCTA-RGD and NOTA-RGD was compared in mice bearing HT-29 colorectal tumor xenografts. Activity cleared quickly from the blood and muscle tissue with >90% and >70% of the initial activity cleared within the first 40 min, respectively. The majority of activity was observed in the kidney, liver, and tumor tissue. The observed tumor uptake was specific with up to 75% of the tumor uptake blocked when the mice were preinjected with 160 nmol (100 μg) of unlabeled peptide. Uptake observed in the blocked tumors was not significantly different than the background activity observed in muscle tissue. The only significant difference between the two (68)Ga-radiolabeled bioconjugates in vivo was the kidney uptake. (68)Ga-radiolabeled PCTA-RGD had significantly lower (p < 0.05) kidney uptake (1.1 ± 0.5%) at 2 h postinjection compared to (68)Ga-radiolabeled NOTA-RGD (2.7 ± 1.3%). Overall, (68)Ga-radiolabeled PCTA-RGD and NOTA-RGD performed similarly, but the lower kidney uptake for (68)Ga-radiolabeled PCTA-RGD may be advantageous in some imaging applications. 10.1021/bc300348d
    Gd3TCAS2: An Aquated Gd(3+)-Thiacalix[4]arene Sandwich Cluster with Extremely Slow Ligand Substitution Kinetics. Iki Nobuhiko,Boros Eszter,Nakamura Mami,Baba Ryo,Caravan Peter Inorganic chemistry In aqueous solution, Gd(3+) and thiacalix[4]arene-p-tetrasulfonate (TCAS) form the complex [Gd3TCAS2](7-), in which a trinuclear Gd(3+) core is sandwiched by two TCAS ligands. Acid-catalyzed dissociation reactions, as well as transmetalation and ligand exchange with physiological concentrations of Zn(2+) and phosphate, showed [Gd3TCAS2](7-) to be extremely inert compared to other Gd complexes. Luminescence lifetime measurements of the Tb analogue Tb3TCAS2 allowed estimation of the mean hydration number q to be 2.4 per Tb ion. The longitudinal relaxivity of [Gd3TCAS2](7-) (per Gd(3+)) was r1 = 5.83 mM(-1) s(-1) at 20 Hz (37 °C, pH 7.4); however, this relaxivity was limited by an extremely slow water exchange rate that was 5 orders of magnitude slower than the Gd(3+) aqua ion. Binding to serum albumin resulted in no relaxivity increase owing to the extremely slow water exchange kinetics. The slow dissociation and water exchange kinetics of [Gd3TCAS2](7-) can be attributed to the very rigid coordination geometry. 10.1021/acs.inorgchem.6b00241
    Structure-relaxivity relationships of serum albumin targeted MRI probes based on a single amino acid Gd complex. Boros Eszter,Caravan Peter Journal of medicinal chemistry The Gd(III) complex of DO3A-N-α-aminopropionate, Gd(DOTAla), was used to generate a small library of putative MRI probes targeted to human serum albumin (HSA). Ten compounds were synthesized via multistep organic synthesis, and the corresponding Gd complexes were investigated for their affinity to HSA, lipophilicity, and relaxivity in the absence and presence of HSA. Negative charge and moderate lipophilicity correlate with increased HSA affinity and relaxivity. 10.1021/jm4000177
    Classification of Metal-based Drugs According to Their Mechanisms of Action. Boros Eszter,Dyson Paul J,Gasser Gilles Chem Metal-based drugs and imaging agents are extensively used in the clinic for the treatment and diagnosis of cancers and a wide range of other diseases. The current clinical arsenal of compounds operate via a limited number of mechanisms, whereas new putative compounds explore alternative mechanisms of action, which could potentially bring new chemotherapeutic approaches into the clinic. In this review, metal-based drugs and imaging agents are characterized according to their primary mode of action and the key properties and features of each class of compounds are defined, wherever possible. A better understanding of the roles played by metal compounds at a mechanistic level will help to deliver new metal-based therapies to the clinic, by providing an alternative, targeted and rational approach, to supplement non-targeted screening of novel chemical entities for biological activity. 10.1016/j.chempr.2019.10.013
    Nuclear and Optical Bimodal Imaging Probes Using Sequential Assembly: A Perspective. Ahn Shin Hye,Boros Eszter Cancer biotherapy & radiopharmaceuticals New, targeted imaging tracers enable improved diagnosis, staging, and planning of treatment of disease and represent an important step toward personalized medicine applications. The combination of radioisotopes for nuclear imaging with fluorophores for fluorescence imaging provides the possibility to noninvasively assess disease burden in a patient using positron emission tomography/single-photon emission computed tomography, followed by fluorescence imaging-assisted surgical intervention in close succession. Probes enabling imaging with both modalities pose a design, synthesis, and pharmacokinetics challenge. In this study, the authors strive to summarize recent efforts toward optimized, discrete, bimodal probes as well as a perspective on future directions of this burgeoning subfield of targeted imaging probe development. 10.1089/cbr.2018.2499
    Intramolecular Hydrogen Bonding Restricts Gd-Aqua-Ligand Dynamics. Boros Eszter,Srinivas Raja,Kim Hee-Kyung,Raitsimring Arnold M,Astashkin Andrei V,Poluektov Oleg G,Niklas Jens,Horning Andrew D,Tidor Bruce,Caravan Peter Angewandte Chemie (International ed. in English) Aqua ligands can undergo rapid internal rotation about the M-O bond. For magnetic resonance contrast agents, this rotation results in diminished relaxivity. Herein, we show that an intramolecular hydrogen bond to the aqua ligand can reduce this internal rotation and increase relaxivity. Molecular modeling was used to design a series of four Gd complexes capable of forming an intramolecular H-bond to the coordinated water ligand, and these complexes had anomalously high relaxivities compared to similar complexes lacking a H-bond acceptor. Molecular dynamics simulations supported the formation of a stable intramolecular H-bond, while alternative hypotheses that could explain the higher relaxivity were systematically ruled out. Intramolecular H-bonding represents a useful strategy to limit internal water rotational motion and increase relaxivity of Gd complexes. 10.1002/anie.201702274
    MR imaging probes: design and applications. Boros Eszter,Gale Eric M,Caravan Peter Dalton transactions (Cambridge, England : 2003) This perspective outlines strategies towards the development of MR imaging probes that our lab has explored over the last 15 years. Namely, we discuss methods to enhance the signal generating capacity of MR probes and how to achieve tissue specificity through protein targeting or probe activation within the tissue microenvironment. 10.1039/c4dt02958e
    Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracers. Boros Eszter,Holland Jason P Journal of labelled compounds & radiopharmaceuticals Radiometals are becoming increasingly accessible and are utilized frequently in the design of radiotracers for imaging and therapy. Nuclear properties ranging from the emission of γ-rays and β -particles (imaging) to Auger electron and β and α-particles (therapy) in combination with long half-lives are ideally matched with the relatively long biological half-life of monoclonal antibodies in vivo. Radiometal labeling of antibodies requires the incorporation of a metal chelate onto the monoclonal antibody. This chelate must coordinate the metal under mild conditions required for the handling of antibodies, as well as provide high kinetic, thermodynamic, and metabolic stability once the metal ion is coordinated to prevent release of the radionuclide before the target site is reached in vivo. Herein, we review the role of different radiometals that have found applications of the design of radiolabeled antibodies for imaging and radioimmunotherapy. Each radionuclide is described regarding its nuclear synthesis, coordinative preference, and radiolabeling properties with commonly used and novel chelates, as well as examples of their preclinical and clinical applications. An overview of recent trends in antibody-based radiopharmaceuticals is provided to spur continued development of the chemistry and application of radiometals for imaging and therapy. 10.1002/jlcr.3590