COMPARISON OF 2 COMPARTMENTAL-MODELS FOR DESCRIBING RECEPTOR-LIGAND KINETICS AND RECEPTOR AVAILABILITY IN MULTIPLE INJECTION PET STUDIES

The goal of research with receptor ligands and PET is the characteriza tion of an in vivo system that measures rates of association and disso ciation of a ligand receptor complex and the density of available bind ing sites. It has been suggested that multiple injection studies of ra dioactive ligand are more likely to identify model parameters than are single injection studies. Typically, at least one of the late injecti ons is at a low specific activity (SA), so that part of the positron e mission tomography (PET) curve reflects ligand dissociation. Low SA in jections and the attendant reductions in receptor availability, howeve r, may violate tracer kinetic assumptions, namely, tracer may no longe r be in steady state with the total (labeled and unlabeled) ligand. Ti ssue response becomes critically dependent on the dose of total ligand , and an accurate description of the cold ligand in the tissue is need ed to properly model the system. Two alternative models have been appl ied to the receptor modeling problem, which reduces to describing the time-varying number of available receptor sites. The first (Huang et a l., 1989) contains only compartments for the hot ligand, 'hot only' (H O), but indirectly accounts for the action of cold ligand at receptor sites via SA. The second stipulates separate compartments for the hot and cold ligands,'hot and cold' (HC), thus explicitly calculating avai lable number of receptors. We examined these models and contrasted the ir abilities to predict PET activity, receptor availability, and SA in each tissue compartment. For multiple injection studies, the models c onsistently predicted different PET activities-especially following th e third injection. Only for very high rate constants were the models i dentical for multiple injections. In one case, simulated PET curves we re quite similar, but discrepancies appeared in predictions of recepto r availability. The HO model predicted nonphysiological changes in the availability of receptor sites and introduced errors of 30-60% into e stimates of B'(max) for test data. We, therefore, strongly recommend t he use of the HC model for all analyses of multiple injection PET stud ies.