Measuring DAT occupancy and density changes due to administration of cocaine analogs by displacement of [F-18]FECNT

Objectives Administration of cocaine increases monoamine neurotransmitter levels and dopamine transporter (DAT) occupancy is strongly correlated with its reinforcing effects. Cocaine analogs of similar binding affinity but less reinforcing have been proposed as possible therapies for cocaine abuse. This work develops a kinetic model based on the generalized reference tissue model (GRTM) to estimate DAT occupancy and density changes when the drug half-time is short compared to the imaging duration.

Methods Two anesthetized squirrel monkeys underwent four separate [F-18]FECNT PET scans. A baseline scan was acquired immediately after injection of [F-18]FECNT. At 90min post injection, one of four drugs (0.3mg/kg RTI-150, 0.3mg/kg RTI-177, 1.0mg/kg RTI-336, or 1.0mg/kg cocaine) was injected and followed by an additional 120min of scanning totaling 210min. Occupancy was estimated with a modified GRTM employing 6 parameters (R,k2,k3,k4,k3',b) by comparing binding potential pre and post injection. The modification included a time dependent, k3'(t), which is the pre injection k3 multiplied by an exponential with time constant b to account for drug clearance during the scan.

Results The RTI compounds were best fit with a 5 parameter model that does not impose a time varying modifier to k3' suggesting these drugs continuously compete with [F-18]FECNT over the scan duration. Cocaine required 6 parameters, occupying 95% of DAT immediately following injection and decreasing to an apparent 60% occupancy plateau at 180min. Because cocaine has undergone 2 clearance half-times by 90min, the 60% apparent occupancy reflects a new state following cocaine injection that has 60% fewer transporters available for binding for at least 120 min.

Conclusions This work presents evidence that cocaine alters the number of available transporters for binding that persists after cocaine clears the system. The biological clearance time of RTI compounds were too long to permit observation of a similar effect over the scan duration