Somatostatin receptors, particularly the somatostatin receptor subtype 2 (sst2), are found on many tumor types. Ii this proposal, we shall focus on the development of radiohalogenated octreotide conjugates and related peptides as radiodiagnostics and therapeutics for medulloblastoma. Recent studies have demonstrated that the concentratior of sst2 on human medulloblastoma is extremely high, even higher than on neuroendocrine tumors. Medulloblastoma is the most frequent central nervous system tumor in children with dismal outcome. There is no effective treatment for this disease, making the development of more specific and selective diagnostics anc therapeutics for medulloblastoma of high clinical significance. Finally, medulloblastoma appears to be an idea clinical setting for exploiting the radiobiological advantages of a-particles such as those emitted by 211At Ou hypothesis is that octreotide conjugates and labeling methods for these peptides which maximize the trapping of the radiohalogen within the tumor cell will enhance tumor retention and tumor-to-normal organ ratios, thereby improving their clinical potential as diagnostic and therapeutic agents.
Our specific aims are: 1) To synthesizL he2' 'At-labeled octreotide analogues [N-(3-[211 At]astatobenzoyl)-D-phe1]octreotide and 5[211 'At]astato-nicotinoylD-phe1]octreotide and compare their properties to the corresponding iodo analogues; 2) To label glycate octreotide and octreotate conjugates with radioiodine nuclides and 211At; peptide conjugates of glucose, maltose and maltotriose will be investigated; 3) To adapt two strategies originally developed for labeling intemalizini antibodies - D-amino acid linkers and acylation agents bearing polar substituents - for labeling octreotide analogue with 211At and radioiodine nuclides; 4) To evaluate the potential utility of promising 211 octreotide conjugates in comparison with their radioiodinated analogues as diagnostic and therapeutic radiopharmaceuticals. The proposed in vitro studies include characterization of binding, internalization and catabolism; the proposed in vivo studies include evaluation of tissue distribution, dosimetry, catabolism as well as therapeutic efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA091927-01
Application #
6359752
Study Section
Special Emphasis Panel (ZRG1-DMG (35))
Program Officer
Stone, Helen B
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$287,595
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Kuan, Chien-Tsun; Wikstrand, Carol J; McLendon, Roger E et al. (2009) Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma. Hybridoma (Larchmt) 28:389-403
Vaidyanathan, Ganesan; Zalutsky, Michael R (2008) Astatine Radiopharmaceuticals: Prospects and Problems. Curr Radiopharm 1:177
Vaidyanathan, G; Affleck, D J; Schottelius, M et al. (2006) Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor. Bioconjug Chem 17:195-203
Akabani, Gamal; Carlin, Sean; Welsh, Phil et al. (2006) In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction. Nucl Med Biol 33:333-47
Pozzi, Oscar R; Zalutsky, Michael R (2005) Radiopharmaceutical chemistry of targeted radiotherapeutics, part 1: effects of solvent on the degradation of radiohalogenation precursors by 211At alpha-particles. J Nucl Med 46:700-6
Vaidyanathan, G; Affleck, D J; Zalutsky, M R (2005) No-carrier-added synthesis of a 4-methyl-substituted meta-iodobenzylguanidine analogue. Appl Radiat Isot 62:435-40
Pozzi, Oscar R; Zalutsky, Michael R (2005) Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 2: radiolytic effects of 211At alpha-particles influence N-succinimidyl 3-211AT-astatobenzoate synthesis. J Nucl Med 46:1393-400
Vaidyanathan, Ganesan; Shankar, Sriram; Affleck, Donna J et al. (2004) Meta-iodobenzylguanidine derivatives containing a second guanidine moiety. Bioorg Med Chem 12:1649-56
Shankar, Sriram; Vaidyanathan, Ganesan; Affleck, Donna J et al. (2004) Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent. Nucl Med Biol 31:909-19
Vaidyanathan, Ganesan; Welsh, Philip C; Vitorello, Katia C et al. (2004) A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells. Eur J Nucl Med Mol Imaging 31:1362-70

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