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Quantitative Analysis of ¹¹C-Verapamil Transfer at the Human Blood–Brain Barrier for Evaluation of P-glycoprotein Function

¹ Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; ² Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; ³ Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan; and ⁴ Department of Radiochemistry, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan

Correspondence: For correspondence or reprints contact: Hiroshi Ito, MD, PhD, Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan.E-mail: hito{at}nirs.go.jp

P-glycoprotein in the blood–brain barrier (BBB) has been found to be associated with several types of neurologic damage. ¹¹C-Verapamil has been used for in vivo imaging of P-glycoprotein function in the BBB by PET, but metabolites in plasma complicate the quantitative analysis of human studies. In this study, we validated the quantification methods of ¹¹C-verapamil transfer from plasma to the brain in humans. Methods: The transfer rate constant from plasma to the brain, K₁, was estimated by nonlinear least squares (NLS) with a 2-input compartment model, including the permeation of the main metabolite in plasma at the BBB, and with a 1-input compartment model using only 15-min data that contained little metabolite in plasma. K₁ was also estimated by graphical analysis of an integration plot that uses only early-time data, before the appearance of metabolites, and the estimated K₁ was compared with that obtained by the NLS method. In the simulation study, the reliability of parameter estimates in the graphical analysis method was investigated for various values of rate constants, time ranges of parameter estimations, and noise levels. Results: ¹¹C-Verapamil in plasma gradually converted to its metabolites, and about 45% of the radioactivity in the plasma specimen was associated with ¹¹C-verapamil metabolites at 30 min after injection. Although K₁ estimated from graphical analysis was slightly smaller than that by NLS, there was strong correlation among the K₁ values obtained by these 3 methods. In the simulation study, for graphical analysis, the differences between the true and mean of K₁ estimates became larger and the coefficient of variation (COV) of K₁ estimates became smaller as the end time of linear regression became later. The COV of graphical analysis was almost equal to that of NLS with the 1-input compartment model. Conclusion: The transfer of ¹¹C-verapamil from plasma to the brain was able to be quantitatively estimated by graphical analysis because this method can provide K₁ from the data of the initial few minutes without considering the effect of the metabolites in plasma.

Key Words: ¹¹C-verapamil • PET • P-glycoprotein • blood–brain barrier • transfer rate constant

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