A computerized Infusion Pump for control of tissue tracer concentration during Positron Emission Tomography in vivo Pharmacokinetic/Pharmacodynamic measurements

Based on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.Various kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02.The UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.Functional imaging for the assessment of the in vivo pharmacokinetics and pharmacodynamics (PK/PD) of drugs either preclinically or in early clinical trials has become an important step in pharmacological research and drug development. Positron Emission Tomography (PET) is a noninvasive imaging tool that allows the assessment of PK/PD parameters directly at the level of the drug target, as opposed to traditional models where tissue PK/PD is estimated indirectly via knowledge of plasma concentrations and/or through measurements of biomarkers as indicators of target modulation. With the administration of radiolabeled drugs, PET allows the direct measurement of tissue concentration of radioactivity, and through knowledge of the specific radioactivity, ratio of radioactivity concentration and concentration of non-radioactive compound, the drug concentration kinetic profile can be obtained with high accuracy. Alterna