Positron emission tomography and target-controlled infusion for precise modulation of brain drug concentration.

INTRODUCTION: There are several instances when it is desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration of anesthetic agents to different desired levels fitting to different needs during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from animals. METHODS: A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [11C]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n=6) were monitored in a microPET scanner during the whole experiment to verify resulting brain kinetic curves. RESULTS: A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118+/-6 ng/ml. As the infusion rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56+/-4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107+/-7 ng/ml was rapidly achieved. CONCLUSION: The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration.

Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [(11)C]CIT and target controlled infusion.

INTRODUCTION: Occupancy-over-time was determined for two dopamine transporter (DAT) inhibitors through modeling of their ability to displace the PET ligand [(11)C]CIT. The tracer was held at a pseudo steady state in a reference tissue by target controlled infusion. METHODS: Rhesus monkeys (n = 5) were given [(11)C]CIT and studied with a PET scanner. Tracer uptake in the reference tissue cerebellum was held at a pseudo steady state by use of target controlled infusion. The pharmacokinetics/pharmacodynamics(PK/PD) of [(11)C]CIT was assessed through the simplified reference tissue model (SRTM). Bupropion (n = 2) and GBR-12909 (n = 2) receptor occupancies were estimated through modeling of their effects on [(11)C]CIT displacement. RESULTS: There was a high uptake of [(11)C]CIT in striatum, which contains a high DAT density. The reference tissue cerebellum had a comparatively low uptake. The modeling of [(11)C]CIT PK/PD properties in striatum showed high binding potential (BP = 5.34 ± 0.78). Both DAT inhibitors caused immediate displacement of [(11)C]CIT after administration. The occupancy-over-time was modeled as a mono-exponential function, describing initial maximal occupancy (Occ(0)) and rate of ligand-receptor dissociation (k(off)). GBR-12909 showed irreversible binding (k(off) = 0) after an initial occupancy of 76.1%. Bupropion had a higher initial occupancy (84.5%) followed by a release half-life of 33 minutes (k(off) = 0.021). CONCLUSIONS: The proposed model can be used for assessment of in-vivo occupancy-over-time of DAT ligands by use of target controlled infusion of [(11)C]CIT. The concept of assessing drug-receptor interactions by studying perturbations of a PET tracer from a pseudo steady state can be transferred to other CNS systems.