UNLABELLED: P-glycoprotein in the blood-brain barrier (BBB) has been found to be associated with several types of neurologic damage. (11)C-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 (11)C-verapamil transfer from plasma to the brain in humans. METHODS: The transfer rate constant from plasma to the brain, K(1), 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. K(1) was also estimated by graphical analysis of an integration plot that uses only early-time data, before the appearance of metabolites, and the estimated K(1) 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: (11)C-Verapamil in plasma gradually converted to its metabolites, and about 45% of the radioactivity in the plasma specimen was associated with (11)C-verapamil metabolites at 30 min after injection. Although K(1) estimated from graphical analysis was slightly smaller than that by NLS, there was strong correlation among the K(1) values obtained by these 3 methods. In the simulation study, for graphical analysis, the differences between the true and mean of K(1) estimates became larger and the coefficient of variation (COV) of K(1) 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 (11)C-verapamil from plasma to the brain was able to be quantitatively estimated by graphical analysis because this method can provide K(1) from the data of the initial few minutes without considering the effect of the metabolites in plasma.
UNLABELLED: P-glycoprotein in the blood-brain barrier (BBB) has been found to be associated with several types of neurologic damage. (11)C-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 (11)C-verapamil transfer from plasma to the brain in humans. METHODS: The transfer rate constant from plasma to the brain, K(1), 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. K(1) was also estimated by graphical analysis of an integration plot that uses only early-time data, before the appearance of metabolites, and the estimated K(1) 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: (11)C-Verapamil in plasma gradually converted to its metabolites, and about 45% of the radioactivity in the plasma specimen was associated with (11)C-verapamil metabolites at 30 min after injection. Although K(1) estimated from graphical analysis was slightly smaller than that by NLS, there was strong correlation among the K(1) values obtained by these 3 methods. In the simulation study, for graphical analysis, the differences between the true and mean of K(1) estimates became larger and the coefficient of variation (COV) of K(1) 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 (11)C-verapamil from plasma to the brain was able to be quantitatively estimated by graphical analysis because this method can provide K(1) from the data of the initial few minutes without considering the effect of the metabolites in plasma.
Authors: Pavitra Kannan; Kyle R Brimacombe; William C Kreisl; Jeih-San Liow; Sami S Zoghbi; Sanjay Telu; Yi Zhang; Victor W Pike; Christer Halldin; Michael M Gottesman; Robert B Innis; Matthew D Hall Journal: Proc Natl Acad Sci U S A Date: 2011-01-24 Impact factor: 11.205
Authors: P Kannan; C John; S S Zoghbi; C Halldin; M M Gottesman; R B Innis; M D Hall Journal: Clin Pharmacol Ther Date: 2009-07-22 Impact factor: 6.875
Authors: Nicholas Seneca; Sami S Zoghbi; Jeih-San Liow; William Kreisl; Peter Herscovitch; Kimberly Jenko; Robert L Gladding; Andrew Taku; Victor W Pike; Robert B Innis Journal: J Nucl Med Date: 2009-04-16 Impact factor: 10.057
Authors: Jens P Bankstahl; Claudia Kuntner; Aiman Abrahim; Rudolf Karch; Johann Stanek; Thomas Wanek; Wolfgang Wadsak; Kurt Kletter; Markus Müller; Wolfgang Löscher; Oliver Langer Journal: J Nucl Med Date: 2008-07-16 Impact factor: 10.057