Astatine 211 & Radioiodine Labeled Octreotide Conjugates

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DESCRIPTION (Provided by Applicant): 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.