Pharmaco-Kinetic Modeling

Modeling of Physiological Processes

Physical and physiological principles are used to analyze dynamic and metabolic processes (e.g. blood flow and oxygen metabolism) resulting in mathematical descriptions that predict the results of experiments in terms of physiologically relevant parameters. In the case of positron emission tomography, it has been possible to develop models of a wide variety of processes, including regional blood flow, oxygen metabolism and end-capillary PO2, the dopamine re-uptake system, and protein synthesis.
In collaboration with Dr. Fischman and the pharmaceutical industry, PET kinetic modeling methods have been extended to allow measurements of pharmacokinetics and pharmacodynamics in both animal and human subjects. Related techniques have now been applied to dynamic MRI spectroscopy to provide quantitative analysis of the TCA cycle.

Compartment Modeling of Tracer Pharmacokinetics

Compartment Modeling of Tracer Pharmacokinetics
Example of compartment modeling from input function, to TAC to parametric images

Compartment modeling can be used to quantify physiology or metabolism using PET images. Our research is focused on applying methods of compartment modeling analysis to estimate kinetic rate constants in cardiac or brain PET studies.

Pharmacokinetic evaluation of the tau radiotracer [18F]T807

[18F]T807 is a promising PET tracer that targets tau deposits, which have been linked to both Alzheimer’s disease and traumatic brain injury.

Our work involves a full characterization of [18F]T807 kinetics using the metabolite corrected arterial input function. We are also exploring the use of graphical and reference region based methods for simplified quantitation of [18F]T807 distribution.

Dopamine Release for Functional Evaluation

Dopamine Release for Functional Evaluation
Simulations results for two doses of amphetamine.
Fig. 4: Simulations were performed for two doses of amphetamine (0.6 and 1 mg/kg) that were assumed to increase synaptic dopamine 10-fold and 20-fold (blue curves), respectively. Simulation results for fMRI signal were employed as GLM analysis regressors (red curves) to describe data from whole putamen (black points) with a single scaling factor after correction for baseline drift using a quadratic polynomial. The functional map from one session (M3, 1 mg/kg) shows voxels that were significantly correlated with the regressor and exhibited maximal changes in CBV greater than 5%.

With the state-of-the-art imaging technologies of combination PET-MR scanners, we will study the relationship between functional MRI and the dopamine release detected with PET under functional stimulation in the brain.

Below is a sample figure from a recent publication in NeuroImage, entitled “Receptor­ based model for dopamine­ induced fMRI signal“. Research was performed in collaboration with the MGH Athinoula A. Martinos Center and the MIT Electrical Engineering and Computer Science

Reprinted from NeuroImage, 75, Joseph B. Mandeville, Christin Y.M. Sander, Bruce G. Jenkins, Jacob M. Hooker, Ciprian Catana, Wim Vanduffel, Nathaniel M. Alpert, Bruce R. Rosen, Marc D. Normandin, Receptor­ based model for dopamine­ induced fMRI signal, 46-57, Copyright 2013, with permission from Elsevier.

Kinetic Modeling of monocyte trafficking

Kinetic Modeling of monocyte trafficking

Using chemistries developed in the lab, we are able to track monocytes through PET imaging over the timescale of up to a week with 89Zr-nanoparticles. Below is a sample figure from one of our recent publications, in press at Angewandte Chemie.

Kinetics of Monocytes, PET images and plots

Figure 2. PET PK. a) A representative maximum intensity project (MIP) PET/CT image of a mouse at 30 minutes after injection, with 89Zr-FH in heart blood pool and carotid arteries. b) A 4 h hepatic phase image where 89Zr-FH is predominately in the liver, with limited uptake in the renal node. With 24 h (d) and 7 d (e) images, nodal radioactivity has increased further. e) Time dependent SUV’s for organs shown as means and standard deviations, n=4. Nodal SUV’s fit to a mono-exponential equation, while liver and spleen fit a biexponential with constants given in Table 1. f) Blood radioactivity (following an injection of 89Zr-FH) and blood 1/T2 relaxation rates (following an injection of FH) as a function of time after injection.

M.D. Normandin, H. Yuan, M.Q. Wilks, H.H. Chen, J.M. Kinsella, H. Cho, N.J. Guehl, N. Absi-Halabi, S.M. Hosseini, G. El Fakhri, D.E. Sosnovik, and L. Josephson. “Heat Induced radiolabeled Nanoparticles Allow PET-derived Monocyte Tracking.” Angewandte Chemie, 2015; 127(44)

Software Development for Quantitative Image Analysis

One of our research interests is to establish software that is publicly available for imaging researchers for image quantification and modeling analysis. New toolboxes written for MATLAB will be developed in the future to streamline the image analysis.

Cognitive Activation Studies using Positron Emission Tomography

Cognitive Activation Studies using Positron Emission Tomography

Over the last 7 years we have established a program that tests modern theories of cognition using PET imaging and brain activation paradigms. The program conducts research in high-level vision, memory, language, and psychiatric conditions. Thirty four publications and a number of important insights have resulted from this collaborative research.