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Pharmacokinetic Analysis of the Positron Emission Tomography Radiotracer [18F]ML-10 in Glioblastoma Multiforme Brain Tumors.

Oborski, Matthew (2018) Pharmacokinetic Analysis of the Positron Emission Tomography Radiotracer [18F]ML-10 in Glioblastoma Multiforme Brain Tumors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Conventional approaches to radiologic response assessment are inadequate for early therapy response assessment (ETRA) of glioblastoma multiforme (GBM), as they rely on slowly changing measures of therapeutic effect, e.g., changes in tumor size or in contrast enhancement on magnetic resonance imaging (MRI). Positron emission tomography (PET) imaging of GBM glucose metabolism using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) has exhibited some success in diagnostic imaging of GBM; however, false-positive uptake caused by inflammation at the tumor site as well as high background uptake in uninvolved brain tissue limits its use for ETRA.

2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid ([18F]ML-10) has recently been proposed as a PET radiotracer for imaging apoptosis. Molecular imaging of apoptosis is an attractive approach to ETRA of GBM, as it would provide a direct measure of therapeutic effect and a framework within which to interpret and compare efficacies of competing therapies. Previous studies have demonstrated the safety and bioavailability of [18F]ML-10 in healthy humans. However, the pharmacokinetic (PK) properties of [18F]ML-10 have not been evaluated.

This dissertation examines the PK properties of [18F]ML-10 in a cohort of human subjects receiving treatment for GBM. [18F]ML-10 time-course in GBM was studied on a whole tumor and voxelwise level. [18F]ML-10 uptake was modeled as the response of a linear system using the radiotracer concentration in blood (measured from the PET image) as the input function (IF). In the whole tumor analysis, candidate models for the IF and GBM impulse response function (IRF) were fit simultaneously using a maximum likelihood approach. The relative merits of the joint IF/IRF models were compared using the Akaike information criterion and model parameter estimability considerations. Spectral analysis was performed to support model selection and provide alternative estimates of standard PK uptake measures. The selected IF/IRF models were further interpreted through tissue compartmental modeling. Standard PK measures of radiotracer uptake derived from models were evaluated for their utility in ETRA for a limited number of subjects. Finally, GBM heterogeneity in response to therapy was evaluated through a voxelwise analysis of [18F]ML-10 uptake. Comparison was made between [18F]ML-10 uptake at an ETRA time-point and later change in tumor cellularity measured using diffusion weighted MRI.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Oborski, Matthewmattoborski@gmail.commjo29
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLaymon, Charlescml14@pitt.educml14
Committee MemberFerris, Robertferrrl@upmc.edurlf1
Committee MemberIbrahim, Tamertsi2@pitt.edutsi2
Committee MemberLoughlin, Patrickloughlin@pitt.eduloughlin
Committee MemberMountz, Jamesmountzjm@upmc.edujmm92
Committee MemberPrice, Juliejcprice@mgh.harvard.edupricjc
Date: 25 September 2018
Date Type: Publication
Defense Date: 29 June 2018
Approval Date: 25 September 2018
Submission Date: 18 July 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 351
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: [18F]ML-10; Early Therapy Response Assessment; Glioblastoma Multiforme; Positron Emission Tomography; Pharmacokinetic Modeling
Date Deposited: 25 Sep 2018 14:53
Last Modified: 25 Sep 2018 14:53
URI: http://d-scholarship.pitt.edu/id/eprint/35013

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  • Pharmacokinetic Analysis of the Positron Emission Tomography Radiotracer [18F]ML-10 in Glioblastoma Multiforme Brain Tumors. (deposited 25 Sep 2018 14:53) [Currently Displayed]

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