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Objectives In PET studies for neuroreceptors, tracer kinetics are described by the two-tissue compartment model (2-TCM), and binding parameters, including the total distribution volume (V T), non-displaceable distribution volume (V ND), and binding potential (BPND), can be determined from model parameters estimated by kinetic analysis. The stability of binding parameter estimates depends on the kinetic characteristics of radioligands. To describe these kinetic characteristics, we previously developed a two-phase graphic plot analysis in which V ND and V T can be estimated from the x-intercept of regression lines for early and delayed phases, respectively. In this study, we applied this graphic plot analysis to visual evaluation of the kinetic characteristics of radioligands for neuroreceptors, and investigated a relationship between the shape of these graphic plots and the stability of binding parameters estimated by the kinetic analysis with 2-TCM in simulated brain tissue time-activity curves (TACs) with various binding parameters. Methods 90-min TACs were generated with the arterial input function and assumed kinetic parameters according to 2-TCM. Graphic plot analysis was applied to these simulated TACs, and the curvature of the plot for each TAC was evaluated visually. TACs with several noise levels were also generated with various kinetic parameters, and the bias and variation of binding parameters estimated by kinetic analysis were calculated in each TAC. These bias and variation were compared with the shape of graphic plots. Results The graphic plots showed larger curvature for TACs with higher specific binding and slower dissociation of specific binding. The quartile deviations of V ND and BPND determined by kinetic analysis were smaller for radioligands with slow dissociation. Conclusions The larger curvature of graphic plots for radioligands with slow dissociation might indicate a stable determination of V ND and BPND by kinetic analysis. For investigation of the kinetics of radioligands, such kinetic characteristics should be considered.

Positron emission tomography (PET) with 18F-FE-PE2I is useful for investigating the function of dopamine transporter, and kinetics of 18F-FE-PE2I could be described by standard two-tissue compartment model (2CM) using plasma input function. In this study, we investigated the feasibility of semi-quantitative methods for estimating binding potential (BPND) and transporter occupancy to shorten the scan period and to reduce the effect of statistical noise on quantitative outcomes using computer simulation and human PET studies with 18F-FE-PE2I. In the simulations, time-activity curves (TACs) for the putamen with a wide range of BPND were generated. In these TACs, BPNDs were estimated by standardized uptake value ratio (SUVR) using various integration intervals and the simplified reference tissue model (SRTM) with the cerebellum as reference region, and reduction of BPND assuming transporter occupancy by antipsychotics was calculated from BPND obtained from TACs with various BPND values. These estimates were evaluated by comparison with those of 2CM. In human studies with normal volunteers, BPNDs were estimated in the caudate and putamen using SUVR and SRTM with the cerebellar reference region, and compared with BPND by standard 2CM. In the simulations, BPND estimated by SUVR with late time frames and SRTM showed linear correlation with those by 2CM, although the estimates by SUVR were overestimated and affected by the cerebral blood flow as BPND became higher. As for transporter occupancy, SRTM showed higher linearity with 2CM and less effect of statistical noise than the SUVR method. In human studies, BPND by SRTM and SUVR with late time frames showed good correlation with BPND by 2CM. Although SRTM is more reliable than the SUVR method for BPND and occupancy estimation, SUVR using late time frames has the potential to provide practical indices of BPND and occupancy with a shorter scan period.

To investigate the effects of the clinical dose of clarithromycin, a substrate of P-glycoprotein (P-gp), on P-gp function using positron emission tomography (PET) with [(11)C]verapamil. METHODS: Two PET scanning with [(11)C]verapamil were performed before and after administration of 400 mg/day of clarithromycin on each of four healthy male subjects. The rate constant of transfer from plasma to brain (K (1)) was estimated by integration plot method. RESULTS: K (1) values of [(11)C]verapamil before administration of clarithromycin were 0.042-0.070 mL/cm(3)/min (0.054 +/- 0.012) and those after administration were 0.037-0.066 mL/cm(3)/min (0.055 +/- 0.013). No significant change in K (1) values of [(11)C]verapamil was observed between before and after administration of clarithromycin (P = 0.85). CONCLUSION: K (1) values of [(11)C]verapamil were not changed by clinical dose administration of clarithromycin, suggesting that a clinical dose of clarithromycin does not affect P-gp function at the blood-brain barrier.

To reduce variance of the total volume of distribution (V T) image, we improved likelihood estimation in graphical analysis (LEGA) for dynamic positron emission tomography (PET) images using maximum a posteriori (MAP). In our proposed MAP estimation in graphical analysis (MEGA), a set of time-activity curves (TACs) was formed with V T varying in physiological range as a template, and then the most similar TAC was sought out for a given measured TAC in a feature space. In simulation, MEGA was compared with other three methods, Logan graphical analysis (GA), multilinear analysis (MA1), and LEGA using 500 noisy TACs, under each of seven physiological conditions (from 9.9 to 61.5 of V T). PET studies of [11C]SA4503 were performed in three healthy volunteers. In clinical studies, the V T images estimated from MEGA were compared with region of interest (ROI) estimates from a nonlinear least square (NLS) fitting over four brain regions. In the simulation study, the estimated V T by GA had a large underestimation (y = 0.27x + 8.72, r 2 = 0.87). Applying the other methods (MA1, LEGA, and MEGA), these noise-induced biases were improved (y = 0.80x + 4.04, r 2 = 0.98; y = 0.85x + 3.05, r 2 = 0.99; y = 0.96x + 1.21, r 2 = 0.99, respectively). MA1 and LEGA produced increased variance of the estimated V T in clinical studies. However, MEGA improved signal-to-noise ratio (SNR) in V T images with linear correlations between ROI estimates with NLS (y = 0.87x + 5.1, r 2 = 0.96). MEGA was validated as an alternative strategy of LEGA to improve estimates of V T in clinical PET imaging.

Positron emission tomography (PET) with ¹⁸F-FE-PE2I is useful for investigating the function of dopamine transporter, and kinetics of ¹⁸F-FE-PE2I could be described by standard two-tissue compartment model (2CM) using plasma input function. In this study, we investigated the feasibility of semi-quantitative methods for estimating binding potential (BPND) and transporter occupancy to shorten the scan period and to reduce the effect of statistical noise on quantitative outcomes using computer simulation and human PET studies with ¹⁸F-FE-PE2I.In the simulations, time-activity curves (TACs) for the putamen with a wide range of BPND were generated. In these TACs, BPNDs were estimated by standardized uptake value ratio (SUVR) using various integration intervals and the simplified reference tissue model (SRTM) with the cerebellum as reference region, and reduction of BPND assuming transporter occupancy by antipsychotics was calculated from BPND obtained from TACs with various BPND values. These estimates were evaluated by comparison with those of 2CM. In human studies with normal volunteers, BPNDs were estimated in the caudate and putamen using SUVR and SRTM with the cerebellar reference region, and compared with BPND by standard 2CM.In the simulations, BPND estimated by SUVR with late time frames and SRTM showed linear correlation with those by 2CM, although the estimates by SUVR were overestimated and affected by the cerebral blood flow as BPND became higher. As for transporter occupancy, SRTM showed higher linearity with 2CM and less effect of statistical noise than the SUVR method. In human studies, BPND by SRTM and SUVR with late time frames showed good correlation with BPND by 2CM.Although SRTM is more reliable than the SUVR method for BPND and occupancy estimation, SUVR using late time frames has the potential to provide practical indices of BPND and occupancy with a shorter scan period.

OBJECTIVE: Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [(11)C]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [(11)C]PE2I. METHODS: Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [(11)C]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V (T)). The distribution volume ratio (DVR) was calculated as the ratio of V (T) in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed. RESULTS: The highest [(11)C]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [(11)C]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions. CONCLUSION: Due to the [(11)C]PE2I kinetics in the cerebellum and limited scan duration for (11)C, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.

To investigate the effects of the clinical dose of clarithromycin, a substrate of P-glycoprotein (P-gp), on P-gp function using positron emission tomography (PET) with [11C]verapamil.Two PET scanning with [11C]verapamil were performed before and after administration of 400 mg/day of clarithromycin on each of four healthy male subjects. The rate constant of transfer from plasma to brain (K1) was estimated by integration plot method.K1 values of [11C]verapamil before administration of clarithromycin were 0.042-0.070 mL/cm3/min (0.054 ± 0.012) and those after administration were 0.037-0.066 mL/cm3/min (0.055 ± 0.013). No significant change in K1 values of [11C]verapamil was observed between before and after administration of clarithromycin (P = 0.85).K1 values of [11C]verapamil were not changed by clinical dose administration of clarithromycin, suggesting that a clinical dose of clarithromycin does not affect P-gp function at the blood-brain barrier.

OBJECTIVES: Both reconstruction algorithms, filtered backprojection (FBP) and ordered subsets expectation maximization (OSEM), are widely used in clinical positron emission tomography (PET) studies. Image reconstruction for most neurotransmission PET scan data is performed by FBP, while image reconstruction for whole-body [18F]FDG scan data is usually performed by OSEM. Although several investigators have compared FBP and OSEM in terms of the quantification of regional radioactivity and physiological parameters calculated from PET data, only a few studies have compared the two reconstruction algorithms in PET studies that estimate neurotransmission, i.e., neuroreceptor and neurotransporter binding. In this study we compared mean regional radioactivity concentration in the late phase and binding potential (BP) between FBP and OSEM algorithms in neurotransmission PET studies for [11C]raclopride and [11C]DASB. METHODS: Dynamic PET scans with [11C]raclopride in 3-dimensional mode were performed on seven healthy subjects. Dynamic PET scans with [11C]DASB in 2-dimensional mode were performed on another seven subjects. OSEM images were post-filtered so that its transverse spatial resolution became similar to that of FBP with the same Hanning filter (Kernel FWHM 6 mm). In both PET studies we calculated the BP of [11C]raclopride and [11C]DASB by a reference tissue model for each ROI (region of interest). RESULTS: There was no significant difference in mean regional radioactivity concentration between FBP and OSEM for [11C]raclopride and [11C]DASB. Only +2.4 - +3.2%, but still a significant difference in BP of [11C]raclopride between FBP and OSEM was observed in the striatum. There was no significant difference in BP between FBP and OSEM in other than the striatum for [11C]raclopride and in all regions for [11C]DASB. In addition, there was no significant difference in root mean square error between FBP and OSEM when BP was calculated. CONCLUSIONS: The BP values were similar between FBP and OSEM algorithms with [11C]raclopride and [11C]DASB. This study indicates that OSEM can be used for human neurotransmission PET studies for calculating BP although OSEM was not necessarily superior to FBP in the present study.

The present study was carried out to investigate the time course of [11C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [11C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [11C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [11C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [11C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [11C]pyrilamine. Based on the rat data, the contribution of 11C-labeled metabolites to total [11C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [11C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [11C]pyrilamine by brain tissue itself. Therefore, [11C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [11C]pyrilamine binding to histamine H1 receptors.

A beta microprobe was successfully applied to monitor arterial input function for quantification of regional cerebral blood flow (rCBF) in the monkey brain with (15)O-water and positron emission tomography (PET). The sensitivity of the probe was approximately 0.83 to 1.67 cps/kBq/ml depending on the studies. A preliminary study was performed to find a suitable use and to evaluate the performance of the system and data analysis procedure. The results showed that dispersion correction of measured input function was unnecessary if microprobes were connected directly to the arterial catheter. Then multiple CBF measurements were done in three monkeys under anesthesia. Identical regions of interest were placed with the aid of magnetic resonance imaging (MRI) of each monkey and rCBF values were estimated. Estimated rCBFs were reproducible for several measurements. The mean CBF value for a pentobarbital anesthetized monkey was 46.0 ml/min/100 g (PaCO2 = 46.3 mmHg). This shows that the use of the beta microprobe for quantification of rCBF with PET was validated. The lack of a need for dispersion correction of observed input function is an advantage with the beta microprobe system because the probes are small enough to be placed near the arterial sampling site.