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Dallas, TX, United States

Coman D.,Yale University | Kiefer G.E.,Macrocyclics | Rothman D.L.,Yale University | Sherry A.D.,University of Texas Southwestern Medical Center | And 2 more authors.
NMR in Biomedicine

Responsive contrast agents (RCAs) composed of lanthanide(III) ion (Ln 3+) complexes with a variety of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA 4-) derivatives have shown great potential as molecular imaging agents for MR. A variety of LnDOTA-tetraamide complexes have been demonstrated as RCAs for molecular imaging using chemical exchange saturation transfer (CEST). The CEST method detects proton exchange between bulk water and any exchangeable sites on the ligand itself or an inner sphere of bound water that is shifted by a paramagnetic Ln 3+ ion bound in the core of the macrocycle. It has also been shown that molecular imaging is possible when the RCA itself is observed (i.e. not its effect on bulk water) using a method called biosensor imaging of redundant deviation in shifts (BIRDS). The BIRDS method utilizes redundant information stored in the nonexchangeable proton resonances emanating from the paramagnetic RCA for ambient factors such as temperature and/or pH. Thus, CEST and BIRDS rely on exchangeable and nonexchangeable protons, respectively, for biosensing. We posited that it would be feasible to combine these two biosensing features into the same RCA (i.e. dual CEST and BIRDS properties). A complex between europium(III) ion (Eu 3+) and DOTA-tetraglycinate [DOTA-(gly)] was used to demonstrate that its CEST characteristics are preserved, while its BIRDS properties are also detectable. The in vitro temperature sensitivity of EuDOTA-(gly) was used to show that qualitative MR contrast with CEST can be calibrated using quantitative MR mapping with BIRDS, thereby enabling quantitative molecular imaging at high spatial resolution. © 2011 John Wiley & Sons, Ltd. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 159.64K | Year: 2003

DESCRIPTION (provided by applicant): Copper-64 has applications for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. One of the goals of this SBIR is to study two novel 64Cu-labeled phosphonate macrocyclic complexes for their uptake in normal bone. A second goal of this proposal is to demonstrate the potential of the lead compound, 64Cu-DO3P (1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)), as a radiopharmaceutical for bone imaging using positron emission tomography (PET) and therapy for bone metastases. Our hypothesis is that 64Cu-labeled macrocyclic complexes containing phosphonate groups will adhere to normal bone and bone metastases and imaging and therapy will be accomplished with the same agent. The advantage of this class of agents for bone metastasis therapy is that dosimetry with the same agent will be determined with PET prior to therapy. We will evaluate, by microPET imaging, 64Cu-DO3P in two mouse models of bone metastases using the same cell line (B 16F10 mouse melanoma tumor cells). Therapeutic studies will be performed in one of the metastasis models to determine if higher doses of 64Cu-DO3P will ablate the bone tumors. Our Specific Aims are as follows: l. To synthesize sufficient amounts (up to 1g) of the methanephosponate derivative DO3A-P and the bisphosphonate amide derivative DO3A-BPA. We will develop an HPLC method for DO3P, DO3A-P and DO3A-BPA, and the copper complexes of these ligands to establish purity levels. 2. To perform microPET imaging studies on 64Cu-DO3P in an osteolytic melanoma bone metastasis model to see the progression of tumors to the skeleton over the course of tumor growth. 3. To evaluate 64Cu-labeled complexes from Aim 1 for their in vivo stability and bone uptake compared to the lead compound, 64Cu-DO3P. If either 64Cu-DO3A-P or 64Cu-DO3A-BPA has greater uptake in bone and more optimal clearance than 64Cu-DO3P, then that agent will undergo further investigation in PET imaging studies in the bone metastasis model. 4. To perform preliminary experiments to investigate if 64Cu-DO3P, or the most optimal 64Cu complex determined from Aim 3, has therapeutic efficacy in two mouse bone metastasis model compared to unlabeled Cu-DO3P and uncomplexed DO3P.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 182.23K | Year: 2002

DESCRIPTION (provided by applicant): In this project, we will develop new gadolinium-based contrast agents that are exquisitely sensitive to pH and establish their feasibility in determining extracellular pH in vivo using a standard clinical MRI protocol. Extracellular pH is clearly an important parameter to know in neoplastic tissues because it has been shown that acidosis can modulate the cytotoxicity of some anticancer drugs, influence thermal radio-sensitization and enhance the killing effects of heat. We recently demonstrated that a simple gadolinium complex containing a single, slowly exchanging, inner-sphere water molecule senses pH via catalytic exchange of bound water protons. This unique chemical feature offers a major advantage over other known gadolinium complexes because proton relaxivity is not limited by molecular exchange of the bound water. This means that complexes with water relaxivity values higher than previously achieved can be made by attaching existing small molecule pH sensitive agent to polymers of increasing size. We have licensed this technology from the University of Texas at Dallas and through the current funding mechanism intend to create even more pH responsive MRI agents, demonstrate their utility in vivo in animal models, and make them commercially to the biomedical research community. PROPOSED COMMERCIAL APPLICATION: Magnetic resonance imaging is widely used to detect tumors in humans, yet little physiological information is gained in a normal MRI exam. We plan to develop new pH sensitive contrast agents that can be safely injected into patients to determine the extracellular pH of tumors using a standard imaging protocol. We believe this could become a standard protopcol in clinical oncology.

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

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. Source

Ait-Mohand S.,Universite de Sherbrooke | Fournier P.,Universite de Sherbrooke | Dumulon-Perreault V.,Universite de Sherbrooke | Kiefer G.E.,Macrocyclics | And 4 more authors.
Bioconjugate Chemistry

Several bifunctional chelates (BFCs) were investigated as carriers of 64Cu for PET imaging. The most widely used chelator for 64Cu labeling of BFCs is DOTA (1,4,7,10-tetraazacyclododecane-N, N′,N″,N″-tretraacetic acid), even though this complex exhibits only moderate in vivo stability. In this study, we prepared a series of alternative chelator-peptide conjugates labeled with 64Cu, measured in vitro receptor binding affinities in human breast cancer T47D cells expressing the gastrin-releasing peptide receptor (GRPR) and compared their in vivo stability in mice. DOTA-, NOTA-(1,4,7-triazacyclononane-1,4,7-triacetic acid), PCTA-(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9- triacetic acid), and Oxo-DO3A-(1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) peptide conjugates were prepared using H 2N-Aoc-[d-Tyr 6,βAla 11,Thi 13,Nle 14] bombesin(6-14) (BBN) as a peptide template. The BBN moiety was selected since it binds with high affinity to the GRPR, which is overexpressed on human breast cancer cells. A convenient synthetic approach for the attachment of aniline-BFC to peptides on solid support is also presented. To facilitate the attachment of the aniline-PCTA and aniline-Oxo-DO3A to the peptide via an amide bond, a succinyl spacer was introduced at the N-terminus of BBN. The partially protected aniline-BFC (p-H 2N-Bn-PCTA(Ot-Bu) 3 or p-H 2N-Bn-DO3A(Ot-Bu) 3) was then coupled to the resulting N-terminal carboxylic acid preactivated with DEPBT/ClHOBt on resin. After cleavage and purification, the peptide-conjugates were labeled with 64Cu using [ 64Cu]Cu(OAc) 2 in 0.1 M ammonium acetate buffer at 100 °C for 15 min. Labeling efficacy was >90% for all peptides; Oxo-DO3A-BBN was incubated an additional 150 min at 100 °C to achieve this high yield. Specific activities varied from 76 to 101 TBq/mmol. Competition assays on T47D cells showed that all BFC-BBN complexes retained high affinity for the GRPR. All BFC-BBN 64Cu-conjugates were stable for over 20 h when incubated at 37 °C in mouse plasma samples. However, in vivo, only 37% of the 64Cu/Oxo-DO3A complex remained intact after 20 h while the 64Cu/DOTA-BBN complex was completely demetalated. In contrast, both 64Cu/NOTA- and 64Cu/PCTA-BBN conjugates remained stable during the 20 h time period. Our results indicate that it is possible to successfully conjugate aniline-BFC with peptide on solid support. Our data also show that 64Cu-labeled NOTA- and PCTA-BBN peptide conjugates are promising radiotracers for PET imaging of many human cancers overexpressing the GRP receptor. © 2011 American Chemical Society. Source

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