The mission of the Developmental Therapeutics Program is the identification and development of novel synthetics and natural products as potential anti-cancer agents. Toward this mission the contract is devoted to the preparation of radiolabeled agents needed by the various programs of the Division of Cancer Treatment and Diagnosis.The contract encompasses two major activities: synthesis and repository-related activities. Thelatter includes deep freeze storage, analysis, purification and shipping of radiolabeled compounds. About 70% of the annual budget is utilized for synthesis and the remainder is required to cover expenses incurred to maintain the repository-related activities including the deep freeze storage facility (-70 degrees Celsius) radio-safety and radio-waste disposal. The estimated value of the stored compounds now numbering 137 exceeds $1,000,000.The compounds selected for syntheses involve both synthetics and natural products and cover a wide variety of chemical structures and complexity. The major focus will be on the synthesis of 3H-labeled compounds of high specific activity as well as 14C-labeled compounds. New radiolabeled syntheses are initiated upon program request derived from RAID and the Drug Development Group (DDG) initiatives.The radiolabeled compounds are used primarily to support preclinical pharmacology, toxicology, and mechanism of action studies. These studies are critical for successful drug development since they help the investigators define important properties, such as the in vivo fate of the parent compound. Furthermore, radiolabeled agents are used to identify metabolites, select the optimal route of drug administration, and monitor the biological disposition of compounds. Knowledge of these characteristics of developmental drugs and the identification of their metabolites help medicinal chemists to rationally design analogs or derivatives with improved physico-chemical properties, such as stability, solubility, partition coefficient as well as improved pharmacokinetics, such as half life, tissue distribution, bio-availability. In the case of highly potent compounds, chromatographic and spectroscopic techniques are of limited value for the measurement of drug levels, particularly for compounds that lack strong chromophores. Radiolabeled compounds overcome these shortcomings, since they permit their detection and identification at very low concentrations.
