Approaches to the Design and Evaluation of Compounds for BNCT

Abstract

The development of new and more effective agents for neutron capture therapy (NCT) continues to remain an important and ongoing problem as we strive to prepare compounds which possess greater and greater specificity for tumor versus contiguous normal tissues¹. The problem that the synthetic chemist encounters in the rational development of such compounds is the paucity of information available as to the biochemical and physiological differences between normal and malignant cells that will allow the selective incorporation of the neutron absorber into tumor cells and their stroma. Cancer chemotherapeutic agents² which have been used clinically for more than 40 years, have been evaluated for their tumoricidal activity and not on the basis of concentration differentials that may exist between tumor and adjacent normal tissues. On the other hand, concentration differentials have been very important in the development of radiopharmaceuticals, which have been used largely as diagnostic agents for malignancies, but in such instances only trace amounts, from a chemical standpoint, are administered³. Therefore, it is understandable that their clinical pharmacokinetic parameters may be considerably different from those observed, where significant amounts of compound are administered. This is certainly the requirement for NCT. Thus, the key questions for the development of new compounds for NCT are: (1) what is the rational basis for designing specific tumor-targeting agents, and (2) how should such structures be evaluated from an in vitro and in vivo standpoint in order to ascertain their potential utility in NCT?