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Ferreira C.L.,Nordion | Yapp D.T.T.,BC Cancer Agency | Mandel D.,Nordion | Gill R.K.,BC Cancer Agency | And 5 more authors.
Bioconjugate Chemistry | Year: 2012

In this study, a bifunctional version of the chelate PCTA was compared to the analogous NOTA derivative for peptide conjugation, 68Ga 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 αvβ 3 receptor. Both PCTA-RGD and NOTA-RGD could be radiolabeled with 68Ga 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 68Ga-radiolabeled conjugates were >90% stable in serum and in the presence of excess apo-transferrin over 4 h; 68Ga-PCTA-RGD did have slightly lower stability than 68Ga-NOTA-RGD, 93 ± 2% compared to 98 ± 1%, at the 4 h time point. Finally, the tumor and nontarget organ uptake and clearance of 68Ga-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 68Ga-radiolabeled bioconjugates in vivo was the kidney uptake. 68Ga-radiolabeled PCTA-RGD had significantly lower (p < 0.05) kidney uptake (1.1 ± 0.5%) at 2 h postinjection compared to 68Ga-radiolabeled NOTA-RGD (2.7 ± 1.3%). Overall, 68Ga-radiolabeled PCTA-RGD and NOTA-RGD performed similarly, but the lower kidney uptake for 68Ga-radiolabeled PCTA-RGD may be advantageous in some imaging applications. © 2012 American Chemical Society.


Boros E.,University of British Columbia | Boros E.,TRIUMF Laboratory Particle and Nuclear Physics | Ferreira C.L.,Nordion | Yapp D.T.T.,BC Cancer Agency | And 5 more authors.
Nuclear Medicine and Biology | Year: 2012

Introduction: The rekindled interest in the 68Ga generator as an attractive positron emission tomography generator system has led us and others to investigate novel chelate systems for 68Ga. We have previously reported our findings with the acyclic, rapidly coordinating chelate H 2dedpa and its model derivatives. Methods: In this report, we describe the synthesis of the corresponding bifunctional chelate scaffolds (H 2dp-bb-NCS and H 2dp-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 vβ 3 targeting cyclic pentapeptide cRGDyK (monomeric H 2RGD-1 and dimeric H 2RGD-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 [ 67Ga(RGD-1)] + was more stable (92% after 2 h) than [ 67Ga(RGD-2)] + (73% after 2 h) in a transferrin challenge experiment. IC 50 values for both conjugates (H 2RGD-1 and H 2RGD-2) and nonconjugated RGD were determined in a cell-based competitive binding assay with 125I-echistatin using U87MG cells, where enhanced specific binding was observed for the multivalent H 2RGD-2 conjugate compared to the monovalent H 2RGD-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 [ 68Ga(RGD-1)] + and [ 68Ga(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 [ 67Ga(RGD-1)] +, 1.46 with [ 67Ga(RGD-2)] +), both conjugates display high uptake in blood. Conclusions: We have successfully synthesized and applied the first bifunctional versions of H 2dedpa for conjugation to a targeting vector and subsequent imaging of the corresponding conjugates. © 2012 Elsevier Inc.


Boros E.,University of British Columbia | Boros E.,TRIUMF Laboratory Particle and Nuclear Physics | Cawthray J.F.,University of British Columbia | Ferreira C.L.,Nordion | And 3 more authors.
Inorganic Chemistry | Year: 2012

Studies of the acyclic ligand scaffold H 2dedpa and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for 67/68Ga, the chelate is now shown to coordinate 64Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered solution). The hexadentate, distorted octahedral coordination of H 2dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltammetry determined the reduction potential of [Cu(dedpa)] to be below values found for common bioreductants. Reduction and reoxidation were irreversible but reproducible, indicating a potential change of coordination mode upon reduction of Cu(II) to Cu(I). The thermodynamic stability constant log K CuL was determined to be 19.16(5), comparable to other frequently used 64Cu chelates. Serum stability of the 64Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGD1)]) and 6% ([Cu(RGD2)]) transchelation at the same time point. © 2012 American Chemical Society.


Bailey G.A.,University of British Columbia | Price E.W.,University of British Columbia | Price E.W.,TRIUMF Laboratory Particle and Nuclear Physics | Zeglis B.M.,Sloan Kettering Cancer Center | And 8 more authors.
Inorganic Chemistry | Year: 2012

Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H2azapa and the radiometals 64Cu, 67Ga, 111In, and 177Lu have established its significant versatile potential as an alternative to 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H2azapa radiolabels quantitatively with 64Cu, 67Ga, 111In, and 177Lu in 10 min at room temperature. In vitro competition experiments with human blood serum show that 64Cu remained predominantly chelate-bound, with only 2% transchelated to serum proteins after 20 h. Biodistribution experiments with [64Cu(azapa)] in mice reveal uptake in various organs, particularly in the liver, lungs, heart, intestines, and kidneys. When compared to [ 64Cu(DOTA)]2-, the lipophilic neutral [ 64Cu(azapa)] was cleared through the gastrointestinal tract and accumulated in the liver, which is common for lipophilic compounds or free 64Cu. The chelator H2azapa is a model complex for a click-based bifunctional chelating agent, and the lipophilic benzyl "place-holders" will be replaced by hydrophilic peptides to modulate the pharmacokinetics and direct activity away from the liver and gut. The solid-state molecular structure of [In(azapa)(H2O)][ClO4] reveals a very rare eight-coordinate distorted square antiprismatic geometry with one triazole arm bound, and the structure of [64Cu(azapa)] shows a distorted octahedral geometry. The present study demonstrates significant potential for bioconjugates of H2azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H2azapa easily modified into a variety of bioconjugates. H2azapa is a versatile addition to the "pa" family, joining the previously published H2dedpa (67/68Ga and 64Cu), H4octapa (111In, 177Lu, and 90Y), and H5decapa ( 225Ac) to cover a wide range of important nuclides. © 2012 American Chemical Society.


Boros E.,University of British Columbia | Boros E.,TRIUMF Laboratory Particle and Nuclear Physics | Lin Y.-H.S.,University of British Columbia | Ferreira C.L.,Nordion | And 4 more authors.
Dalton Transactions | Year: 2011

We describe the synthesis of the dip (di-picolyl-carboxylate) bifunctional chelator system, capable of fast coordination of Cu2+, 64Cu2+ and Co2+, as well as the [M(CO) 3]+-core (M = 99mTc, Re); it displays a variety of binding modes - tridentate when protected, tetradentate when deprotected. Syntheses of both the benzyl-nitro derivative and the benzyl-amino derivatives are described. The latter was coupled to biotin to show the viability of the system for functionalization with biomolecules. Besides coordination chemistry with stable isotopes, we also present labelling data with 64Cu and 99mTc, as well as in vitro stability studies. © 2011 The Royal Society of Chemistry.

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