Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals

Cai, Zhengxin; Anderson, Carolyn J.

doi:10.1002/jlcr.3165

Cited by 95 publications

(96 citation statements)

References 65 publications

(113 reference statements)

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“…The half-life of 64 Cu (12.7 h) is also compatible with the pharmacokinetics of peptides (1) or antibody fragments (2,3) that recognize tumor-associated receptors overexpressed on cancer cells. Moreover, many different bifunctional chelators that strongly complex 64 Cu have been developed for conjugation to these targeting ligands (4). In addition to its positron emission, 64 Cu emits b 2 particles, Auger and internal conversion (IC) electrons, and g-photons.…”

mentioning

confidence: 99%

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

2016

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64 Cu emits positrons as well as b 2 particles and Auger and internal conversion electrons useful for radiotherapy. Our objective was to model the cellular dosimetry of 64 Cu under different geometries commonly used to study the cytotoxic effects of 64 Cu. Methods: Monte Carlo N-Particle (MCNP) was used to simulate the transport of all particles emitted by 64 Cu from the cell surface (CS), cytoplasm (Cy), or nucleus (N) of a single cell; monolayer in a well (radius 5 0.32-1.74 cm); or a sphere (radius 5 50-6,000 mm) of cells to calculate S values. The radius of the cell and N ranged from 5 to 12 mm and 2 to 11 mm, respectively. S values were obtained by MIRDcell for comparison. MCF7/HER2-18 cells were exposed in vitro to 64 Culabeled trastuzumab. The subcellular distribution of 64 Cu was measured by cell fractionation. The surviving fraction was determined in a clonogenic assay. Results: The relative differences of MCNP versus MIRDcell self-dose S values (S self ) for 64 Cu ranged from 20.2% to 3.6% for N to N (S N)N ), 2.3% to 8.6% for Cy to N (S N)Cy ), and 212.0% to 7.3% for CS to N (S N)CS ). The relative differences of MCNP versus MIRDcell cross-dose S values were 25.8%-30.6% for a monolayer and 30%-34% for a sphere, respectively. The ratios of S N)N versus S N)Cy and S N)Cy versus S N)CS decreased with increasing ratio of the N of the cell versus radius of the cell and the size of the monolayer or sphere. The surviving fraction of MCF7/HER2-18 cells treated with 64 Cu-labeled trastuzumab (0.016-0.368 MBq/mg, 67 nM) for 18 h versus the absorbed dose followed a linear survival curve with a 5 0.51 6 0.05 Gy 21 and R 2 5 0.8838. This is significantly different from the linear quadratic survival curve of MCF7/ HER2-18 cells exposed to g-rays. Conclusion: MCNP-and MIRDcell-calculated S values agreed well. 64 Cu in the N increases the dose to the N in isolated single cells but has less effect in a cell monolayer or small cluster of cells simulating a micrometastasis, and little effect in a sphere analogous to a tumor xenograft compared with 64 Cu in the Cy or on the CS. The dose deposited by 64 Cu is less effective for cell killing than g-rays. Because it can be routinely produced in a biomedical cyclotron and emits moderate energy positrons (E max 5 0.653 MeV [19%]) that provide good spatial resolution (0.7 mm), 64 Cu is an attractive radionuclide for positron-emission tomography. The half-life of 64 Cu (12.7 h) is also compatible with the pharmacokinetics of peptides (1) or antibody fragments (2,3) that recognize tumor-associated receptors overexpressed on cancer cells. Moreover, many different bifunctional chelators that strongly complex 64 Cu have been developed for conjugation to these targeting ligands (4). In addition to its positron emission, 64 Cu emits b 2 particles, Auger and internal conversion (IC) electrons, and g-photons. The b 2 particles and Auger electrons of 64 Cu have been studied for radiation treatment of tumors (5-9). The maximum b 2 energy of 64 Cu is 0.579 MeV (40%) (10). These partic...

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mentioning

confidence: 99%

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

2016

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“…The cross-bridged cyclam analogue CB-TE2A was reported to greatly improve the stability of copper complexes, 83, 84 and we were able to prepare the CB-TE2A derivative 64 Cu-FBP7 (Figure 11). 85 64 Cu-FBP7 showed a marked improvement compared to 64 Cu-FBP2.…”

Section: Effect Of the Chelator On Thrombus Imaging With 64cu-fbpxmentioning

confidence: 95%

Peptide-based fibrin-targeting probes for thrombus imaging

Oliveira

Caravan

2017

Dalton Trans.

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The development of new methods to image the onset and progression of thrombosis is an unmet need. Non-invasive molecular imaging techniques targeting specific key structures involved in the formation of thrombosis have demonstrated the ability to detect thrombus in different disease state models and in patients. Due to its high concentration in the thrombus and its essential role in thrombus formation, the detection of fibrin is an attractive strategy for identification of thrombosis. Herein we provide an overview of recent and selected fibrin-targeted probes for molecular imaging of thrombosis by magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical techniques. Emphasis is placed on work that our lab has explored over the last 15 years that has resulted in the progression of the fibrin-binding PET probe [64Cu]FBP8 from preclinical studies into human trials.

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“…The coordination chemistry of copper has been well studied and applied for the design of adequate chelates for efficient radiolabeling with 64 Cu [7–10]. Macrocyclic chelates including DOTA (1,4,7,10-tetraazacyclododecane- N , N′ , N″ , N‴ -tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane- N , N ′, N ″, N‴ -tetraacetic acid), and CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid) have been evaluated for 64 Cu-based PET imaging [7–9]. However, the currently available chelates of 64 Cu present limitations for practical use in PET applications including preparation of 64 Cu-radiolabeled chelates under harsh radiolabeling conditions and premature dissociation of 64 Cu from the complexes in vivo [7,9–13].…”

Section: Introductionmentioning

confidence: 99%

“…Macrocyclic chelates including DOTA (1,4,7,10-tetraazacyclododecane- N , N′ , N″ , N‴ -tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane- N , N ′, N ″, N‴ -tetraacetic acid), and CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid) have been evaluated for 64 Cu-based PET imaging [7–9]. However, the currently available chelates of 64 Cu present limitations for practical use in PET applications including preparation of 64 Cu-radiolabeled chelates under harsh radiolabeling conditions and premature dissociation of 64 Cu from the complexes in vivo [7,9–13]. NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) is a TACN (1,4,7-Triazacyclononane)-based hexadentate chelate that is known to form a stable complex with 64 Cu in vitro and in vivo [14].…”

Section: Introductionmentioning

confidence: 99%

Promising bifunctional chelators for copper 64-PET imaging: practical 64Cu radiolabeling and high in vitro and in vivo complex stability

Kang

Sin

et al. 2015

J Biol Inorg Chem

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Positron emission tomography (PET) using copper-64 is a sensitive and non-invasive imaging technique for diagnosis and staging of cancer. A bifunctional chelator that can present rapid radiolabeling kinetics and high complex stability with 64Cu is a critical component for targeted PET imaging. Bifunctional chelates 3p-C-NE3TA, 3p-C-NOTA, and 3p-C-DE4TA were evaluated for complexation kinetics and stability with 64Cu in vitro and in vivo. Hexadentate 3p-C-NOTA and heptadentate 3p-C-NE3TA possess a smaller TACN-based macrocyclic backbone, while nonadentate 3p-C-DE4TA is constructed on a larger CYCLEN-based ring. The frequently explored chelates of 64Cu, octadentate C-DOTA and hexadentate C-NOTA were also comparatively evaluated. Radiolabeling kinetics of bifunctional chelators with 64Cu was assessed under mild conditions. All bifunctional chelates instantly bound to 64Cu in excellent radiolabeling efficiency at room temperature. C-DOTA was less efficient in binding 64Cu than all other chelates. All 64Cu-radiolabeled bifunctional chelates remained stable in human serum without any loss of 64Cu for 2 days. When challenged by an excess amount of EDTA, 64Cu complexes of 3p-C-NE3TA and 3p-C-NOTA were shown to be more stable than 64Cu-C-DOTA and 64Cu-C-DE4TA. 3p-C-NE3TA and 3p-C-NOTA displayed comparable in vitro and in vivo complex stability to 64Cu-C-NOTA. In vivo biodistribution result indicates that the 64Cu-radiolabeled complexes of 3p-C-NOTA and 3p-C-NE3TA possess excellent in vivo complex stability, while 64Cu-3p-C-DE4TA was dissociated as evidenced by high renal and liver retention in mice. The results of in vitro and in vivo studies suggest that the bifunctional chelates 3p-C-NOTA and 3p-C-NE3TA offer excellent chelation chemistry with 64Cu for potential PET imaging applications.

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Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals

Cited by 95 publications

References 65 publications

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

Peptide-based fibrin-targeting probes for thrombus imaging

Promising bifunctional chelators for copper 64-PET imaging: practical 64Cu radiolabeling and high in vitro and in vivo complex stability

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Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals

Cited by 95 publications

References 65 publications

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of64Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of64Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

Peptide-based fibrin-targeting probes for thrombus imaging

Promising bifunctional chelators for copper 64-PET imaging: practical 64Cu radiolabeling and high in vitro and in vivo complex stability

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Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of⁶⁴Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects