Abstract:
:Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH(2)-CO-c(DCys-Phe-Tyr-DAgl(8)(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst(3)-ODN-8) and a sst(2)-selective antagonist (sst(2)-ANT)], for labeling with (111/nat)In. (111/nat)In-DOTA-sst(3)-ODN-8 and (111/nat)In-DOTA-[4-NO(2)-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH(2)] ((111/nat)In-DOTA-sst(2)-ANT) showed high sst(3)- and sst(2)-binding affinity, respectively. They did not trigger sst(3) or sst(2) internalization but prevented agonist-stimulated internalization. (111)In-DOTA-sst(3)-ODN-8 and (111)In-DOTA-sst(2)-ANT were injected intravenously into mice bearing sst(3)- and sst(2)-expressing tumors, and their biodistribution was monitored. In the sst(3)-expressing tumors, strong accumulation of (111)In-DOTA-sst(3)-ODN-8 was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst(3)-ODN-8 blocked uptake. As a control, the potent agonist (111)In-DOTA-[1-Nal(3)]-octreotide, with strong sst(3)-binding and internalization properties showed a much lower and shorter-lasting uptake in sst(3)-expressing tumors. Similarly, (111)In-DOTA-sst(2)-ANT was injected into mice bearing sst(2)-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst(2)-selective agonist (111)In-diethylenetriaminepentaacetic acid-[Tyr(3),Thr(8)]-octreotide ((111)In-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst(3)- or sst(2)-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.
journal_name
Proc Natl Acad Sci U S Aauthors
Ginj M,Zhang H,Waser B,Cescato R,Wild D,Wang X,Erchegyi J,Rivier J,Mäcke HR,Reubi JCdoi
10.1073/pnas.0607761103subject
Has Abstractpub_date
2006-10-31 00:00:00pages
16436-41issue
44eissn
0027-8424issn
1091-6490pii
0607761103journal_volume
103pub_type
杂志文章abstract::The central questions of bacterial ecology and evolution require a method to consistently demarcate, from the vast and diverse set of bacterial cells within a natural community, the groups playing ecologically distinct roles (ecotypes). Because of a lack of theory-based guidelines, current methods in bacterial systema...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::For the purpose of clarifying the magneto-orientation mechanism of several biological membrane systems, xylene-suspended thin-layered single crystals of lecithin, which is a major component of membranes, were subjected to magnetic fields of various strengths, and the orientation behavior of the crystals was analyzed. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.77.12.7232
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Tumor-infiltrating lymphocytes (TIL) obtained from human melanomas can specifically lyse autologous tumor in vitro and mediate tumor regression in vivo. To develop more effective therapeutic reagents and to further understand the T-cell response to tumors, the diversity of T-cell receptors (TCRs) involved in melanoma ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.91.7.2829
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更新日期:1986-04-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1986-07-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Schiff bases of the diamines 1,3-diaminopropane, putrescine, and cadaverine and the polyamines spermidine and spermine with pyridoxal or pyridoxal phosphate occur in human urine, as shown by gas chromatographic/mass spectrometric selected ion-monitoring techniques. By use of synthetic standards, procedures were devise...
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更新日期:1979-12-01 00:00:00
abstract::The proteasome is responsible for degradation of substrates of the ubiquitin pathway. 20S proteasomes are cylindrical particles with subunits arranged in a stack of four heptameric rings. The outer rings are composed of alpha subunits, and the inner rings are composed of beta subunits. A well-characterized archaeal pr...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1997-07-08 00:00:00
abstract::Peroxisomes are eukaryotic organelles critical for plant and human development because they house essential metabolic functions, such as fatty acid β-oxidation. The interacting ATPases PEX1 and PEX6 contribute to peroxisome function by recycling PEX5, a cytosolic receptor needed to import proteins targeted to the pero...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2018-04-03 00:00:00
abstract::Despite structural knowledge of broadly neutralizing monoclonal antibodies (NMAbs) complexed to HIV-1 gp120 and gp41 envelope glycoproteins, virus inactivation mechanisms have been difficult to prove, in part because neutralization assays are complex and were previously not understood. Concordant with recent evidence ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2012-05-15 00:00:00
abstract::Natural-abundance (13)C nuclear magnetic resonance spectra of ten common nucleotides in neutral, aqueous solutions have been determined and interpreted. The spectra of two of these substances were also determined in acidic solutions, and several of the carbon chemical shifts were found to depend markedly on pH. Within...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1970-01-01 00:00:00
abstract::Citrus bacterial canker (CBC) caused by Xanthomonas axonopodis pv. citri (Xac) was first documented in India and Java in the mid 19th century. Since that time, the known distribution of the disease has steadily increased. Concurrent with the dispersion of the pathogen, the diversity of described strains continues to i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2007-11-20 00:00:00
abstract::The estrogen receptor-alpha (ERalpha) is a critical transcription factor that regulates epithelial cell proliferation and ductal morphogenesis during postnatal mammary gland development. Tissue recombination and transplantation studies using the first generation of ERalpha knockout (ERKO) mice suggested that this ster...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0706933104
更新日期:2007-09-11 00:00:00
abstract::A structural and functional model of bacterial nitric oxide reductase (NOR) has been designed by introducing two glutamates (Glu) and three histidines (His) in sperm whale myoglobin. X-ray structural data indicate that the three His and one Glu (V68E) residues bind iron, mimicking the putative Fe(B) site in NOR, while...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.1000526107
更新日期:2010-05-11 00:00:00
abstract::In the troposphere, methanol (CH3OH) is present ubiquitously and second in abundance among organic gases after methane. In the surface ocean, methanol represents a supply of energy and carbon for marine microbes. Here we report direct measurements of air-sea methanol transfer along a ∼10,000-km north-south transect of...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1317840110
更新日期:2013-12-10 00:00:00