ASTATINE-211 RADIOCHEMISTRY: THE DEVELOPMENT OF METHODOLOGIES FOR HIGH ACTIVITY LEVEL RADIOSYNTHESIS

Technical Report · Wed Aug 08 00:00:00 EDT 2012

DOI:https://doi.org/10.2172/1047758· OSTI ID:1047758

ZALUTSKY, MICHAEL R

Targeted radionuclide therapy is emerging as a viable approach for cancer treatment because of its potential for delivering curative doses of radiation to malignant cell populations while sparing normal tissues. Alpha particles such as those emitted by 211At are particularly attractive for this purpose because of their short path length in tissue and high energy, making them highly effective in killing cancer cells. The current impact of targeted radiotherapy in the clinical domain remains limited despite the fact that in many cases, potentially useful molecular targets and labeled compounds have already been identified. Unfortunately, putting these concepts into practice has been impeded by limitations in radiochemistry methodologies. A critical problem is that the synthesis of therapeutic radiopharmaceuticals provides additional challenges in comparison to diagnostic reagents because of the need to perform radio-synthesis at high levels of radioactivity. This is particularly important for {alpha}-particle emitters such as 211At because they deposit large amounts of energy in a highly focal manner. The overall objective of this project is to develop convenient and reproducible radiochemical methodologies for the radiohalogenation of molecules with the {alpha}-particle emitter 211At at the radioactivity levels needed for clinical studies. Our goal is to address two problems in astatine radiochemistry: First, a well known characteristic of 211At chemistry is that yields for electrophilic astatination reactions decline as the time interval after radionuclide isolation from the cyclotron target increases. This is a critical problem that must be addressed if cyclotrons are to be able to efficiently supply 211At to remote users. And second, when the preparation of high levels of 211At-labeled compounds is attempted, the radiochemical yields can be considerably lower than those encountered at tracer dose. For these reasons, clinical evaluation of promising 211At-labeled targeted radiotherapeutics currently is a daunting task. Our central hypothesis is that improvements in 211At radiochemistry are critically dependent on gaining an understanding of and compensating for the effects of radiolysis induced by 211At {alpha}-particles. Because of the widespread interest in labeling antibodies, antibody fragments and peptides with 211At, our proposed work plan will initially focus on reagents that we have developed for this purpose. Part of our strategy is the use of synthetic precursors immobilized on polymeric resins or perfluorous and triarylphosphonium supports. Their use could eliminate the need for a purification step to separate unreacted tin precursor from labeled product and hopefully provide a simple kit technology that could be utilized at other institutions. The specific aims of this project are: (1) To optimze methods for 211At production and isolation of 211At from cyclotron targets; (2) To develop convenient and reproducible methodologies for high activity level and high specific activity radiohalogenation of biomolecules with 211At; (3) to develop a procedure for extending the shelf-life of 211At beyond a few hours so that this radionuclide can be utilized at centers remote from its site of production; and (4) to work out high activity level synthesis methods for utilizing support immobilized tin precursors for 211At labeling. If we are successful in achieving our goals, the radiochemical methodologies that are developed could greatly facilitate the use of 211At-labeled targeted cancer therapeutics in patients, even at institutions that are distant from the few sites currently available for 211At production.

• Research Organization: DUKE UNIVERSITY, DURHAM, NC
• Sponsoring Organization: USDOE Office of Science (SC)
• DOE Contract Number: FG02-08ER64697
• OSTI ID: 1047758
• Report Number(s): DOE/ER/64697-1; TRN: US1204363
• Country of Publication: United States
• Language: English

Related Subjects

43 PARTICLE ACCELERATORS
62 RADIOLOGY AND NUCLEAR MEDICINE
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY
ACTIVITY LEVELS
ALPHA PARTICLES
ANTIBODIES
ASTATINATION
ASTATINE
ASTATINE 211
CHEMISTRY
CYCLOTRONS
NEOPLASMS
PATIENTS
PEPTIDES
PRECURSOR
PURIFICATION
RADIATIONS
RADIOACTIVITY
RADIOCHEMISTRY
RADIOISOTOPES
RADIOLYSIS
RADIOPHARMACEUTICALS
RADIOTHERAPY
RESINS
SYNTHESIS
TARGETS
THERAPY
ALPHA PARTICLES ASTATINE-211 RADIOLYSIS