Non-steady-state measurement of in vivo receptor binding with positron emission tomography: "dose-response" analysis

We previously developed a non-steady-state technique using positron emission tomography (PET) and the radioligand 18F-spiperone (18F-SP) for the measurement of in vivo radioligand-receptor binding in brain. The purpose of this investigation is to determine the sensitivity of this method to alterations in the apparent number of available specific binding sites. Nine studies were performed on the same baboon. The animal was pretreated with varying doses of unlabeled SP (15-600 micrograms) to compete for specific binding sites. The experimental procedure included measurement of regional cerebral blood flow, cerebral blood volume, and the protein binding of 18F-SP in arterial blood. At least 3.5 hr after pretreatment, no-carrier-added 18F-SP (containing less than 3 micrograms SP) was administered intravenously. Sequential PET scans and measurements of arterial-blood radioactivity due to radioligand and its labeled metabolites continued for 3 hr. A 3-compartment model representing the in vivo behavior of radioligand was used to analyze the data. As expected, we found that an index of binding called the combined forward rate constant (which equals the product of the apparent maximum number of available specific binding sites and the association rate constant of radioligand for receptor) declined with increasing dose of unlabeled SP. Other estimated variables including the dissociation rate constant did not change. This demonstrates that our non-steady-state method for estimating radioligand-receptor binding kinetics can detect a decrease in the apparent number of available specific binding sites. This is an important step in the validation of this in vivo receptor binding assay and its subsequent application.