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Evaluation of [¹⁸F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

ABSTRACT: P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [¹⁸F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes ( V_T) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [¹⁸F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral V_T values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [¹⁸F]MC225 was moderate (at 1?h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [¹⁸F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.

SUBMITTER: Savolainen H

PROVIDER: S-EPMC5453451 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Evaluation of [<sup>18</sup>F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

Savolainen Heli H Windhorst Albert D AD Elsinga Philip H PH Cantore Mariangela M Colabufo Nicola A NA Willemsen Antoon Tm AT Luurtsema Gert G

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 4

P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [<sup>18</sup>F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance ...[more]

PMID: 27354093

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Project description:18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region-based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion:18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80-100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.

Project description:PurposeMultidrug resistance (MDR) impedes cancer treatment. Two efflux transporters from the ATP-binding cassette (ABC) family, ABCB1 and ABCG2, may contribute to MDR by restricting the entry of therapeutic drugs into tumor cells. Although a higher expression of these transporters has been correlated with an unfavorable response to chemotherapy, transporter expression does not necessarily correlate with function. In this study, we characterized the pharmacological properties of [18F]AVT-011, a new PET radiotracer for imaging transporter-mediated MDR in tumors.MethodsAVT-011 was radiolabeled with 18F and evaluated with PET imaging in preclinical models. Transport of [18F]AVT-011 by ABCB1 and/or ABCG2 was assessed by measuring its uptake in the brains of wild-type, Abcb1a/b-/-, and Abcg2-/- mice at baseline and after administration of the ABCB1 inhibitor tariquidar (n = 5/group). Metabolism and biodistribution of [18F]AVT-011 were also measured. To measure ABCB1 function in tumors, we performed PET experiments using both [18F]AVT-011 and [18F]FDG in mice bearing orthotopic breast tumors (n = 7-10/group) expressing clinically relevant levels of ABCB1.ResultsAt baseline, brain uptake was highest in Abcb1a/b-/- mice. After tariquidar administration, brain uptake increased 3-fold and 8-fold in wild-type and Abcg2-/- mice, respectively, but did not increase further in Abcb1a/b-/- mice. At 30 min after injection, the radiotracer was > 90% in its parent form and had highest uptake in organs of the hepatobiliary system. Compared with that in drug-sensitive tumors, uptake of [18F]AVT-011 was 32% lower in doxorubicin-resistant tumors with highest ABCB1 expression and increased by 40% with tariquidar administration. Tumor uptake of [18F]FDG did not significantly differ among groups.Conclusion[18F]AVT-011 is a dual ABCB1/ABCG2 substrate radiotracer that can quantify transporter function at the blood-brain barrier and in ABCB1-expressing tumors, making it potentially suitable for clinical imaging of ABCB1-mediated MDR in tumors.

Dataset Information

Evaluation of [¹⁸F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

Publications

Evaluation of [<sup>18</sup>F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

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Evaluation of [18F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

Publications

Evaluation of [<sup>18</sup>F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Evaluation of [¹⁸F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.