~ROJECT TITLE

LABELING OF OCTREOTIDE WITH POSITRON EMITTERS

Grant Number: 2R01CA64475-06 PI Name: Anderson, Carolyn J.

Abstract: The goal of this proposal is to test two hypotheses re- garding the use of radiolabeled peptide hormone receptor ligands for positron emission tomography (PET) imaging and targeted radiotherapy. We have demonstrated the effectiveness of 64Cu (T1/2 = 12.8 h) as a radionuclide for PET imaging and targeted radiotherapy in animal models. From the evaluation of a series of four somatostatin receptor (SSR) analogs, we have determined the optimal peptide sequence for high target uptake (Tyr3-octreotate (Y3-TATE)). In this proposal we will focus on how the structure of the bifunctional chelate (BFC) affects accu- mulation of activity in target and non-target organs. We will ac- complish this by determining the metabolites of 64Cu-labeled BFC-Y3-TATE in vivo in non-target organs and in tumors, as well as the subcellular metabolism in xenografted tumors and tumor cells grown in culture. The first hypotheses we will ad- dress is that copper complexes that are the most difficult to re- duce will demonstrate favorable clearance as Y3-TATE conju- gates, compared to more easily reduced Cu(II) complexes. Our second hypothesis is that dissociation of 64Cu from the BFC- SSR analog may be advantageous in tumor cells, since 64Cu binding to nuclear proteins or DNA may increase its effective- ness of cell killing. Understanding the factors governing the re- tention of 64Cu in target and non-target tissues will aid us in the design of agents that have either more rapid non-target organ clearance or longer residence time in target tissues, or both. De- pending on the clinical situation, there is a need for various im- aging/therapy radionuclide pairs for diagnosing and treating cancer, including 86Y/90Y, 1241/131I, and 64Cu/64Cu (or 61Cu/64Cu). The second objective of this proposal is to use PET imaging to determine dosimetry and tumor response of DOTA-D-Tyrl-octreotate (DOTA-DY1-TATE) labeled with therapeutic amounts of iodine, yttrium and copper isotopes. Us- ing a microPET scanner, which is a high resolution, small-bore PET scanner specifically designed for small animal imaging, we can first determine tumor and normal organ dosimetry, and then monitor the therapeutic response to radiolabeled DOTA-DY1- TATE. Accomplishing this goal will allow us to compare three therapeutic radionuclides labeled to the same agent with respect to efficacy and tumor absorbed dose, and also enable the non- invasive monitoring of non-snhcutaneous tumors, such as liver metastases. The research proposed here will provide an under- standing of the biological behavior of Cu(II) complexes, which is of importance to the field of diagnostic imaging and targeted radiotherapy with copper radionuclides. The research proposed here will also contribute to the development of new radionu- clides for PET and targeted radiotherapy, and further the use of PET as a diagnostic modality prior to and during radiotherapy.

Thesaurus Terms: copper, neoplasm/cancer radionuclide diag- nosis, neoplasm/cancer radionuclide therapy, octreotide, positron emission tomography, radiopharmacology chelating agent, chemical conjugate, chemical synthesis, disease model, hormone receptor, ligand, peptide hormone analog, radiation therapy dos- age, receptor binding athymic mouse, bioimaging/biomedical imaging, iodine, laboratory rat, tissue/cell culture, yttrium

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Washington University Lindell and Skinker Blvd St. Louis, MO 63130 1999 Radiology 18-JUL-94 30-APR-03 National Cancer Institute RNM

~ROJECT TITLf

OCTREOTIDE CONJUGATES FOR DIAGNOSIS AND THERAPY

Grant Number: 5F32CA68699-03 PI Name: Bass, Laura A.

Abstract: One of the goals of this proposed research is to in- crease the number of radioligands available for the labeling with the positron emitting isotope Ga-68 and the readily available gamma-emmiter in- 111. Specifically, efforts will focus on the synthesis of a new diaminoethane dithiol bifunctional chelate that has been found to have the highest stability for Ga(III) and in(m). This chelate be conjugated to a somatostatin analogue, octreotide. Certain cancerous tumors contain a large number of somatostatin receptors, therefore octreotide-radiometal conju- gates can be used to diagnose and treat certain cancers by bind- ing to somatostatin receptor and including a growth inhibitory effect in these tissues. The ability of this diaminoethane dithiol- octreotide- radiometal conjugate to bind somatostatin receptors will be determined using AtT-20 mouse pituitary carcinoma cells. The biodistribution and metabofism the conjugate will be detemained using normal Sprague-Dawley rate. Biodistribution studies will be accomplished by extracting the activity from the various organs and counting each sample using a gamma- counter. The metabolism of the complex will be analyzed using HPLC and radio-TLC. The second goal of this proposal is to evaluate radiolabeled octreotide as a radiotherapeutic agent us- ing tumor-bearing rats. This will involve new production tech- niques for 64Cu at Washington University, the preparation of 64Cu-chelate-octreotide and the manipulation of a rumor-bear- ing rat model for evaluation of therapeutic efficacy of 64Cu. Tu- mor growth inhibition will be evaluated by determining the % survival of animals per week post-treatment. At the time of their death the rats will be dissected and the tumors weighed.

200

Thesaurus Terms: biomaterial development/preparation, chemical conjugate, gastrointestinal agent, octreotide, radio- nuclide, radiotracer, somatostatin copper, disease model, dithiol, drag metabolism, gallium, hormone receptor, indium, neoplasm/cancer chemotherapy, nickel, nonhuman therapy evaluation, pituitary neoplasm, receptor binding high perfor- mance liquid chromatography, laboratory mouse, laboratory rat, scintillation counter, thin layer chromatography

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Washington University Lindell and Skinker Blvd St. Louis, MO 63130 1998 Radiology 29-MAY-98

National Cancer Institute RNM

~ROJECT TITLE

TRAINING IN INNOVATIVE CANCER IMAGING TECHNOLOGIES

Grant Number: 5T32CA65442-04 PI Name: Baum, Stanley

Abstract: The Department of Radiology, in conjunction with the Comprehensive Cancer Center at the University of Pennsyl- vania School of Medicine, is resubmitting a proposal for a Training Program in Innovative Cancer Imaging Technologies. The fundamental goal of the program is to develop quality, in- dependent investigators in Radiology who will focus their sci- eiatific efforts in oncology research, goals which have been strengthened and clarified by the suggested revisions. The pro- gram will prepare postgraduate M.D.s in radiology programs (2/ yr.) for academic radiology research using anatomic and physi- ologic imaging technologies to address issues in the detection, diagnosis, staging, monitoring of treatment, and progression of malignant lesion. In addition to training in the theory and implementation of magnetic resonance (MR), ultrasound, com- puted tomography (CT), optical tomography (OT), positron emission tomography (PET), and single photon emission com- puted tomography (SPECT), the trainees will be exposed to a broad spectrum of imaging research from coil and component design and the development of new technologies, to laboratory studies, translational research and clinical trials utilizing these imaging modalities. Research training will be accomplished through three categories of experiences: (21) preceptor-directed oncology imaging research; (2) laboratory and clinical research structured interactive seminars' and (3) attendance at scientific meetings and appropriate symposia. Participating faculty pre- ceptors have active, funded laboratories and a broad base of ex- perience in imaging and oncology research. The Advisory

Committee to the training program will provide administrative guidance to the program director, evaluate program progress and suggest directions for future programmatic efforts. The progress of the trainees will be monitored carefully, both by the primary preceptor, as well as by the entire participating faculty. The primary research training facility is the Department of Ra- diology which, in addition to extensive MR facilities, has active research groups in metabolic MR, nuclear medicine, medical informatics, medical image processing for tomographic image reconstruction, and a center for the developing technology of optical imaging. In addition, the research and Clinical facilities of the Cancer Center, The Departments of Radiation Oncology, and Biochemistry and Biophysics, and the Hospital of the U.of Penn. will be used by the trainees. The extensive research re- sources in the Department of Radiology and the Cancer Center will ensure quality research training in a scientifically sound and cost-effective manner. This will enable the Department of Radiology to increase the number of young clinical investiga- tors committed to investigative excellence in academic oncol- ogy research using imaging technology.

Thesaurus Terms: There are no thesaurus terms on file for this project.

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

University of Pennsylvania Philadelphia, PA 19104-6380 1999 Radiology 20-JUL-96 30-APR-01 National Cancer Institute CRME

~ROJECT TITLE

SATISFACTION OF SEARCH IN DIAGNOSTIC RADIOLOGY

Grant Number: 5R01CA42453-11 PI Name: Berbaum, Kevin S.

Abstract: The long-term objective of this proposal is to under- stand how the perception of multiple abnormalities in a radiol- ogy examination occurs and to develop strategies for improved diagnostic accuracy and patient outcome. Failure to detect an abnormality is the most common class of error in diagnostic imaging and generally considered the most serious by the med- ical community. Many of these errors have been attributed to 'satisfaction of search,' which occurs when a lesion is not re- ported because discovery of another abnormality has satisfied the goal of the search. The vast majority of technical research and clinical endeavor to reduce error is concentrated in im- proving image quality so that abnormalities are more visible. Another approach is to study, and thereby improve, the inter- pretive process itself. Interpretation is the most crucial, yet

201