Predicting the success of a radiopharmaceutical for in vivo imaging

Summary form only given. This presentation focuses on gathering the critical preclinical data and other steps required to optimize the characteristics of a potential new radioligand for use in vivo. It is based on a critical review of successful and unsuccessful radiopharmaceuticals developed in our center and elsewhere over many years. Included among the factors to be considered for predicting the behavior of a potential radiopharmaceutical in vivo are receptor binding affinity, lipophilicity, nonspecific binding, metabolic stability and ease of radiochemical synthesis. Additional factors include the presence or absence of radioactive metabolites, the attainment of an equilibrium or pseudoequilibrium during the practical imaging time of the radiotracer (i.e., reversibility or irreversibility) during and up to 3 or 4 half lives of the radioisotope, degree of protein binding, agonist or antagonist activity, in vivo toxicity or pharmacologic activity. Additional related factors that could help determine a radiopharmaceutical success include the receptor system to be imaged and its characteristics such as its receptor selectivity to a certain receptor system and that receptor system\´s density, distribution and presence of a "reference region" allowing measurements of nonspecific binding, e.g., in brain. Not only the radiotracer but the target of the radiotracer and other characteristics such as possible internalization versus susceptibility to endogenous receptor ligands are important factors. However, many of these and other factors are yet to be clearly understood. Examples will be provided from the dopamine, serotonin, nicotinic cholinergic and nitrergic transmission systems as well as from the radiosteroid area to describe some of the strengths and pitfalls associated with radiotracer design, development, and their ultimate use in human beings.