Comparative evaluation of the algorithms for parametric mapping of the novel myocardial PET imaging agent 18F-FPTP.

OBJECTIVE: (18F-fluoropentyl)triphenylphosphonium salt (18F-FPTP) is a new promising myocardial PET imaging tracer. It shows high accumulation in cardiomyocytes and rapid clearance from liver. We performed compartmental analysis of 18F-FPTP PET images in rat and evaluated two linear analyses: linear least-squares (LLS) and a basis function method (BFM) for generating parametric images. The minimum dynamic scan duration for kinetic analysis was also investigated and computer simulation undertaken. METHODS: 18F-FPTP dynamic PET (18 min) and CT images were acquired from rats with myocardial infarction (MI) (n = 12). Regions of interest (ROIs) were on the left ventricle, normal myocardium, and MI region. Two-compartment (K 1 and k 2; 2C2P) and three-compartment (K 1-k 3; 3C3P) models with irreversible uptake were compared for goodness-of-fit. Partial volume and spillover correction terms (V a and α = 1 - V a ) were also incorporated. LLS and BFM were applied to ROI- and voxel-based kinetic parameter estimations. Results were compared with the standard ROI-based nonlinear least-squares (NLS) results of the corresponding compartment model. A simulation explored statistical properties of the estimation methods. RESULTS: The 2C2P model was most suitable for describing 18F-FPTP kinetics. Average K 1, k 2, and V a values were, respectively, 6.8 (ml/min/g), 1.1 (min-1), and 0.44 in normal myocardium and 1.4 (ml/min/g), 1.1 (min-1), and 0.32, in MI tissue. Ten minutes of data was sufficient for the estimation. LLS and BFM estimations correlated well with NLS values for the ROI level (K 1: y = 1.06x + 0.13, r 2  = 0.96 and y = 1.13x + 0.08, r 2  = 0.97) and voxel level (K 1: y = 1.22x - 0.30, r 2  = 0.90 and y = 1.26x + 0.00, r 2  = 0.92). Regional distribution of kinetic parametric images (αK 1, K 1, k 2, V a) was physiologically relevant. LLS and BFM showed more robust characteristics than NLS in the simulation. CONCLUSIONS: Fast kinetics and highly specific uptake of 18F-FPTP by myocardium enabled quantitative analysis with the 2C2P model using only the initial 10 min of data. LLS and BFM were feasible for estimating voxel-wise parameters. These two methods will be useful for quantitative evaluation of 18F-FPTP distribution in myocardium and in further studies with different conditions, disease models, and species.

Rapid Hepatobiliary Excretion of Micelle-Encapsulated/Radiolabeled Upconverting Nanoparticles as an Integrated Form.

In the field of nanomedicine, long term accumulation of nanoparticles (NPs) in the mononuclear phagocyte system (MPS) such as liver is the major hurdle in clinical translation. On the other hand, NPs could be excreted via hepatobiliary excretion pathway without overt tissue toxicity. Therefore, it is critical to develop NPs that show favorable excretion property. Herein, we demonstrated that micelle encapsulated (64)Cu-labeled upconverting nanoparticles (micelle encapsulated (64)Cu-NOTA-UCNPs) showed substantial hepatobiliary excretion by in vivo positron emission tomography (PET) and also upconversion luminescence imaging (ULI). Ex vivo biodistribution study reinforced the imaging results by showing clearance of 84% of initial hepatic uptake in 72 hours. Hepatobiliary excretion of the UCNPs was also verified by transmission electron microscopy (TEM) examination. Micelle encapsulated (64)Cu-NOTA-UCNPs could be an optimal bimodal imaging agent owing to quantifiability of (64)Cu, ability of in vivo/ex vivo ULI and good hepatobiliary excretion property.

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory : A dual [(11)C]raclopride and [(18) F]FDG imaging study with aripiprazole.

RATIONALE: The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function. OBJECTIVES: To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D2 receptor occupancy and changes in working memory. METHODS: Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [(11)C]raclopride and [(18) F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [(18) F]FDG scan. RESULTS: The mean (±SD) D2 receptor occupancies were 22.2 ± 16.0 % in the 2 mg group, 35.5 ± 3.6 % in the 5 mg group, 63.2 ± 9.9 % in the 10 mg group and 72.8 ± 2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t = 2.705, df = 14, p = 0.017). Greater striatal D2 receptor occupancy was related to greater decrease in frontal metabolism (r = -0.659, p = 0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r = -0.597, p = 0.019) under the greatest task load. CONCLUSIONS: Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.

Compartmental modeling and simplified quantification of [¹¹C]sertraline distribution in human brain.

Sertraline hydrochloride (Zoloft®, Pfizer) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI). The aims of this study were evaluating its in vivo distribution and kinetic models in human brain. Also, this study was to determine optimal scan duration of dynamic positron emission tomography (PET) for accurate [¹¹C]sertraline kinetic parameters and the feasibility of semi-quantitative approach for assessing distribution volume ratio (DVR). [¹¹C]sertraline dynamic PET and magnetic resonance imaging (MRI) scans were performed in 5 healthy males. Blood sampling were collected for the input function. Tissue time-activity curves (TAC) were obtained in 7 brain regions using MRI. Goodness-of-fit for TAC using simple tissue compartment model (2C2P) and 3-compartment models with irreversible (3C3P) and reversible (3C4P) were compared. Total distribution volume (DV) for each region of interest (ROI) and DVR were calculated. Also, ratio between the standard uptake value (SUV) of each ROI and that of cerebellum (SUVr) was computed and correlated with the DVR. Akaike information criteria analysis showed that the 2C2P was the most suitable model. Average values of K1 (mL/min/g) and k2 (1/min) were 0.54 and 0.012 in putamen. PET scan time longer than 50 min was required for the accurate estimation of DV. SUVr in 50-90 min was well correlated with DVR.

A positron emission tomography microdosing study with sertraline in healthy volunteers.

OBJECTIVE: This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate. METHODS: We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [11C]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state Cmax and AUClast were observed in the 5 - 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the bloodbrain- barrier penetration and distribution of a candidate CNS drug. CONCLUSIONS: This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.