Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET

INTRODUCTION: Neuronal nicotinic acetylcholine receptors (nAChRs), widely distributed in the human brain, are implicated in various neurophysiological processes as well as being particularly affected in neurodegenerative conditions such as Alzheimer's disease. We sought to evaluate a minimally invasive method for quantification of nAChR distribution in the normal human brain, suitable for routine clinical application, using 2[(18)F]F-A-85380 and positron emission tomography (PET). METHODS: Ten normal volunteers (four females and six males, aged 63.40+/-9.22 years) underwent a dynamic 120-min PET scan after injection of 226 MBq 2[(18)F]F-A-85380 along with arterial blood sampling. Regional binding was assessed through standardized uptake value (SUV) and distribution volumes (DV) obtained using both compartmental (DV(2CM)) and graphical analysis (DV(Logan)). A simplified approach to the estimation of DV (DV(simplified)), defined as the region-to-plasma ratio at apparent steady state (90-120 min post injection), was compared with the other quantification approaches. RESULTS: DV(Logan) values were higher than DV(2CM). A strong correlation was observed between DV(simplified), DV(Logan) (r=.94) and DV(2CM) (r=.90) in cortical regions, with lower correlations in thalamus (r=.71 and .82, respectively). Standardized uptake value showed low correlation against DV(Logan) and DV(2CM). CONCLUSION: DV(simplified) determined by the ratio of tissue to metabolite-corrected plasma using a single 90- to 120-min PET acquisition appears acceptable for quantification of cortical nAChR binding with 2[(18)F]F-A-85380 and suitable for clinical application.     

Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans

Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin transporters using (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios. METHODS: Nine subjects were scanned with dynamic (123)I-ADAM SPECT (mean age, 31 y; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated. The specificity of (123)I-ADAM binding was investigated in a blocking experiment. RESULTS: Binding estimates from the simplified reference tissue and Logan reference tissue models correlated tightly with full kinetic modeling when based on a 240- or 360-min dynamic acquisition (r = 0.99); however, there were slight underestimations (3%-5%), especially in high-binding regions. Application of the ratio method to data from 200 to 240 min overestimated specific binding (on average, by 10% +/- 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r = 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k2') from the cerebellum was applied. Intravenously injected citalopram was not associated with a decrease in cerebellar binding. A lipophilic metabolite that did not seem to bind specifically to serotonin transporter was seen in 2 of 7 subjects. CONCLUSION: Serotonin transporter binding with (123)I-ADAM SPECT can be assessed with the Logan model based on a 120-min acquisition when a constant k2' is applied. This model, because it allows for more accurate and less biased binding estimates and thus reduces the required sample size, is advantageous over the ratio method used in clinical studies so far. A single blocking experiment supported the use of the cerebellum as a reference region.     

In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF.

Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2'-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. METHODS: [15O]H2O perfusion scanning was performed before intravenous injection of [18F]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [18F]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). RESULTS: The highest levels of radioactivity were observed in the medial temporal cortex, especially in the hippocampal area. In contrast, the cerebellum and basal ganglia showed low uptake of 18F, in accordance with known 5-HT1A receptor distribution. The calculated binding potentials correlated well with literature values for 5-HT1A receptor densities. The binding potentials for [18F]MPPF were 4-6 times lower than those that have been reported for [carbonyl-1C]-(N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyrid yl) cyclohexane-carboxamide (WAY 100635), indicating that [18F]MPPF has a lower in vivo affinity for 5-HT1A receptors. CONCLUSION: These results confirm that [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in the living human brain. The rapid dissociation from the receptor makes this ligand a possible candidate to monitor changes in endogenous serotonin levels.     

Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis.

PET studies have been performed using the amyloid binding radiotracer Pittsburgh Compound B (PIB). Previous quantitative analyses using arterial blood showed that the Logan graphical analysis using 90 min of emission data (ART90) provided a reliable measure of PIB retention. This work reports on simplified methods of analysis for human PIB imaging. METHODS: PIB PET scans were conducted in 24 subjects (6 Alzheimer's disease [AD], 10 mild cognitive impairment [MCI], 8 controls) with arterial blood sampling. Retest scans were performed on 8 subjects (3 AD, 1 MCI, 4 controls) within 28 d. Data were analyzed over 60 and 90 min using the Logan analysis and (a) metabolite-corrected input functions based on arterial plasma (ART60, ART90), (b) carotid artery time-activity data with a population average metabolite correction (CAR60, CAR90); and (c) cerebellar reference tissue (CER60, CER90). Data also were analyzed using the simplified reference tissue method (SRTM60, SRTM90) and a single-scan method based on late-scan ratios of standardized uptake values (SUVR60, SUVR90). RESULTS: All methods of analysis examined effectively discerned regional differences between AD and control subjects in amyloid-laden cortical regions, although the performance of the simplified methods varied in terms of bias, test-retest variability, intersubject variability, and effect size. CAR90 best agreed with ART90 distribution volume ratio (DVR) measures across brain regions and subject groups and demonstrated satisfactory test-retest variability (+/-7.1% across regions). CER90 and CER60 showed negative biases relative to ART90 in high-DVR subjects but had the lowest test-retest variability. The single-scan SUV-based methods showed the largest effect sizes for AD and control group differences and performed well in terms of intersubject and test-retest variability. CONCLUSION: Of the simplified methods for PIB analysis examined, CAR90 provided DVR measures that were most comparable to ART90; CER90 was the most reproducible and SUVR90 produced the largest effect size. All simplified methods were effective at distinguishing AD and control differences and may be effectively used in the analysis of PIB. SUVR60 data can be obtained with as little as 20 min of PET emission data collection. The relative strengths and limitations of each method must be considered for each experimental design.     

Simplified reference region model for the kinetic analysis of [99mTc]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography.

Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [99mTc]TRODAT-1 in nonhuman primates, obviating the need for blood sampling. A series of dynamic SPET scans were performed on two baboons following the injection of approximately 700 MBq of [99mTc]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reconstructed SPET images were coregistered with magnetic resonance imaging (MRI) scans of the baboons, and regions of interest (ROIs) placed on the striatum, cerebellum and cerebral hemispheres. The ROI data were combined with metabolite-corrected blood data, and fitted to a three-compartment kinetic model using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was derived from the nondisplaceable tissue compartment. In addition, semiquantitative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods generated values for the ratio of the kinetic rate constants k3/k4, which gives an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k3/k4 for the three different analysis techniques for each baboon were: 1.17 +/- 0.21 and 1.12 +/- 0.13 (full kinetic model), 0.93 +/- 0.13 and 0.90 +/- 0.07 (reference region model), and 0.97 +/- 0.18 and 0.92 +/- 0.08 (equilibrium method). The reference region method gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the kinetic data. The reference region model results for k3/k4 correlated very strongly with the full kinetic analysis (r2 = 0.992, P < 0.001), and with the equilibrium model (r2 = 0.88, P = 0.002). The subjectivity inherent in the equilibrium method produces inferior results compared with both kinetic analyses. It is suggested that the self-consistency of the reference region model, which requires no arterial blood sampling, provides a more precise and reliable estimate of the binding of [99mTc]TRODAT-1 to dopamine transporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to distinguish smaller differences in dopaminergic function between patient groups.     

Comparison of 4 methods for quantification of dopamine transporters by SPECT with [123I]IACFT.

2Beta-carbomethoxy-3beta-(4-fluorophenyl)-n-(1-iodoprop-1-en -3-yl) nortropane (IACFT) is a highly selective ligand for dopamine transporter (DAT) sites in the striatum. Recent reports have described the basic kinetics, neurobiology, and imaging properties of [123I]IACFT. This report focuses on the structural (i.e., the ability to produce consistent binding estimates) validity of 4 methods to quantify striatal binding potential (BP) for IACFT. METHODS: Seven healthy volunteers and 8 patients with Parkinson's disease were subjects for this study. Dynamic SPECT images and arterial blood samples were acquired during the 1.5-2 h after injection of 185-370 MBq [123I]IACFT. Plasma radioactivity was analyzed chromatographically to obtain metabolite-corrected arterial input functions. The k3/k4 ratio (BP) for striatal DAT sites was calculated by 4 methods. In the first method, tissue time-activity curves and metabolite-corrected arterial input functions were analyzed by a linear graphic method developed for reversible receptor ligands. The second method was also graphic; however, the occipital cortex time-activity curve was used as the input function. In the third method, the difference between the striatal and occipital cortex time-activity curves at secular equilibrium was taken to represent bound tracer, the occipital cortex time-activity curve was used to represent tracer in the free and nonspecifically bound state, and equilibrium receptor equations were used to determine BP. The fourth method used the occipital cortex time-activity curve to mathematically derive an input function for fitting the striatal time-activity curve and to determine BP. RESULTS: Analysis of the dynamic SPECT data by methods 1 and 2 resulted in highly linear plots (after approximately 15 min), supporting the reversibility of the tracer. A high linear correlation was found for BP determined by all 4 methods. ANOVA showed that methods 1-3 were indistinguishable; method 4 yielded lower BPs than did methods 1-3. CONCLUSION: These results show that BP can be estimated consistently using 4 different methods. This finding lends support to the modeling assumptions and provides methods suitable for clinical investigation.     

Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.

The aim of the present study was to describe a method combining easy implementation in a clinical setting with accuracy and precision in quantification of 123I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl)nortropane (PE2I) binding to brain dopamine transporter. METHODS: Five healthy subjects (mean age, 50 y; range, 40-68 y) were studied twice. In the first experiment, dynamic SPECT data and arterial plasma input curves obtained after 123I-PE2I bolus injection were assessed using Logan, kinetic, transient equilibrium, and peak equilibrium analyses. Accurate and precise determination of BP1 (binding potential times the free fraction in the metabolite-corrected plasma compartment) and BP2 (binding potential times the free fraction in the intracerebral nonspecifically bound compartment) was achieved using Logan analysis and kinetic analysis, with a total study time of 90 min. In the second experiment, (123)I-PE2I was administrated as a combined bolus and constant infusion. The bolus was equivalent to 2.7 h of constant infusion. RESULTS: The bolus-to-infusion ratio of 2.7 h was based on the average terminal clearance rate from plasma in the bolus experiments. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 2 h. Even when an average bolus-to-infusion ratio was used, the striatal BP1 and BP2 values calculated with kinetic analysis (BP1 = 21.1 +/- 1.1; BP2 = 4.1 +/- 0.4) did not significantly differ from those calculated with bolus/infusion analysis (BP1 = 21.0 +/- 1.2; BP2 = 4.3 +/- 0.3). Computer simulations confirmed that a 2-fold difference in terminal clearance rate from plasma translates into only a 10% difference in BP1 and BP2 calculated from 120 to 180 min after tracer administration. CONCLUSION: The bolus/infusion approach allows accurate and precise quantification of 123I-PE2I binding to dopamine transporter and is easily implemented in a clinical setting.     

Quantification of adenosine A<Subscript>2A</Subscript> receptors in the human brain using [<Superscript>11</Superscript>C]TMSX and positron emission tomography

Purpose [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX) is a positron-emitting adenosine A_2A receptor (A2AR) antagonist for visualisation of A2AR distribution by positron emission tomography (PET). The aims of this paper were to use a kinetic model to analyse the behaviour of [¹¹C]TMSX in the brain and to examine the applicability of the Logan plot. We also studied the applicability of a simplified Logan plot by omitting metabolite correction and arterial blood sampling. Methods The centrum semiovale was used as a reference region on the basis of a post-mortem study showing that it has a negligibly low density of A2ARs. Compartmental analysis was performed in five normal subjects. Parametric images of A2AR binding potential (BP) were also generated using a Logan plot with or without metabolite correction and with or without arterial blood sampling. To omit arterial blood sampling, we applied a method to extract the plasma-related information using independent component analysis (EPICA). Results The estimated K ₁/k ₂ was confirmed to be common in the centrum semiovale and main cortices. The three-compartment model was well fitted to the other regions using the fixed value of K ₁/k ₂ estimated from the centrum semiovale. The estimated BPs using the Logan plot matched those derived from compartment analysis. Without the metabolite correction, the estimate of BP underestimated the true value by 5%. The estimated BPs agreed regardless of arterial blood sampling. Conclusion A three-compartment model with a reference region, the centrum semiovale, describes the kinetic behaviour of [¹¹C]TMSX PET images. A2ARs in the human brain can be visualised as a BP image using [¹¹C]TMSX PET without arterial blood sampling.     

Quantification of dopamine transporter density with [18F]FECNT PET in healthy humans

IntroductionFluorine-18 labeled 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([¹⁸ F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [¹⁸ F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [¹⁸ F]FECNT for quantification of DAT density in healthy human brain.MethodsTwelve healthy volunteers underwent 180 min dynamic [¹⁸ F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BP_ND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BP_ND values.ResultsThe kinetics of [¹⁸ F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BP_ND for DAT densities well below that observed in normal volunteers.ConclusionThe kinetics of [¹⁸ F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BP_ND calculated with reference tissue model is proportional to BP_ND calculated from the arterial input model.     

Kinetic modelling of [<Superscript>11</Superscript>C]flumazenil using data-driven methods

Purpose  [¹¹C]Flumazenil (FMZ) is a benzodiazepine receptor antagonist that binds reversibly to central-type gamma-aminobutyric acid (GABA-A) sites. A validated approach for analysis of [¹¹C]FMZ is the invasive one-tissue (1T) compartmental model. However, it would be advantageous to analyse FMZ binding with whole-brain pixel-based methods that do not require a-priori hypotheses regarding preselected regions. Therefore, in this study we compared invasive and noninvasive data-driven methods (Logan graphical analysis, LGA; multilinear reference tissue model, MRTM2; spectral analysis, SA; basis pursuit denoising, BPD) with the 1T model. Methods  We focused on two aspects: (1) replacing the arterial input function analyses with a reference tissue method using the pons as the reference tissue, and (2) shortening the scan protocol from 90 min to 60 min. Dynamic PET scans were conducted in seven healthy volunteers with arterial blood sampling. Distribution volume ratios (DVRs) were selected as the common outcome measure. Results  The SA, LGA with and without arterial input, and MRTM2 agreed best with the 1T model DVR values. The invasive and noninvasive BPD were slightly less well correlated. The full protocol of a 90-min emission data performed better than the 60-min protocol, but the 60-min protocol still delivered useful data, as assessed by the coefficient of variation, and the correlation and bias analyses. Conclusion  This study showed that the SA, LGA and MRTM2 are valid methods for the quantification of benzodiazepine receptor binding with [¹¹C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure.     

Pharmacokinetic analysis of [18F]FAZA in non-small cell lung cancer patients

Purpose

[¹⁸F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [¹⁸F]FAZA studies and to assess the validity of simplified analytical methods.

Methods

Dynamic 70-min [¹⁸F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients. Continuous arterial blood sampling, together with manual arterial and venous sampling, was performed to derive metabolite-corrected plasma input functions. Volumes of interest (VOIs) were defined for tumour, healthy lung muscle and adipose tissue generating [¹⁸F]FAZA time-activity curves (TACs). TACs were analysed using one- and two-tissue compartment models using both metabolite-corrected blood sampler plasma input functions (BSIF) and image-derived plasma input functions (IDIF).

Results

The reversible two-tissue compartment model with blood volume parameter (2T4k+V_B) best described kinetics of [¹⁸F]FAZA in tumours. Volumes of distribution (V_T) obtained using IDIF correlated well with those derived using BSIF (R ²?=?0.82). Venous samples yielded the same radioactivity concentrations as arterial samples for times >50 min post-injection (p.i.). In addition, both plasma to whole blood ratios and parent fractions were essentially the same for venous and arterial samples. Both standardised uptake value (SUV), normalised to lean body mass, and tumour to blood ratio correlated well with V_T (R ²?=?0.77 and R ²?=?0.87, respectively, at 50–60 min p.i.), although a bias was observed at low V_T.

Conclusion

The 2T4k+V_B model provided the best fit to the dynamic [¹⁸F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods.     

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: Part 1--pseudoequilibrium interval and quantification methods.

With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed. METHODS: Nineteen healthy men (mean age +/- SD, 24.4 +/- 3.3 y) were included and separated into 2 groups. Dynamic scans with venous blood sampling from 0 to 470 min after a single bolus injection of (123)I-R91150 was completed for 7 of the 9 subjects included in group A, and in one of them compartmental modeling was performed with an arterial blood input function using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models. Binding potential (BP) using the simplified reference tissue model (SRTM) (BP(SRTM)) and SUR values using TR over time were also calculated. The 10 remaining subjects (group B) underwent a single scan at pseudoequilibrium with the aim of improving the precision of mean normal SUR estimates. Regions of interest in cortical regions and basal ganglia for specific uptake, and in cerebellum for nonspecific uptake, were manually drawn on each subject's MR images and translated to the corresponding SPECT slices after coregistration. RESULTS: The 1TC model correlated well with the 2TC model (BP(2TC) = 1.04.BP(1TC) - 0.01, R(2) = 0.98), and both methods correlated with BP(SRTM) and SUR with little bias (BP(1TC) = 1.10 BP(SRTM) + 0.03, R(2) = 0.98; BP(2TC) = 1.15 BP(SRTM) + 0.01, R(2) = 0.98; BP(SRTM) = 0.99 SUR(mean) + 0.01, R(2) = 0.98). SUR values stabilized from 180 min after injection in most cortical regions, ranging from 0.51 +/- 0.10 in the orbitofrontal region to 0.27 +/- 0.09 in the parietal region. Within-scan and between-subject variability among regions ranged from 10% to 14.8%, and from 18.3% to 35.4%, respectively. CONCLUSION: (123)I-R91150 distribution agrees with autoradiography results, showing highly specific binding in cortical regions. The correlations found among 1TC, 2TC, SRTM, and TR outcome measurements support the use of TR for quantification of 5-HT(2A) receptor binding with (123)I-R91150 SPECT and a simple protocol avoiding arterial blood sampling and serial scanning over time.     

Use of reference tissue models for quantification of histamine H1 receptors in human brain by using positron emission tomography and [11C]doxepin

The aim of the present study is to evaluate the validity of the simplified reference tissue model (SRTM) and of Logan graphical analysis with reference tissue (LGAR) for quantification of histamine H1 receptors (H1Rs) by using positron emission tomography (PET) with [11C]doxepin. These model-based analytic methods (SRTM and LGAR) are compared to Logan graphical analysis (LGA) and to the one-tissue model (1TM), using complete datasets obtained from 5 healthy volunteers. Since HIR concentration in the cerebellum can be regarded as negligibly small, the cerebellum was selected as the reference tissue in the present study. The comparison of binding potential (BP) values estimated by LGAR and 1TM showed good agreement; on the other hand, SRTM turned out to be unstable concerning parameter estimation in several regions of the brain. By including the results of noise analysis, LGAR became a reliable method for parameter estimation of [11C]doxepin data in the cortical regions.     

Reference and target region modeling of [11C]-(R)-PK11195 brain studies.

PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level. METHODS: The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease. RESULTS: The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596). CONCLUSION: Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain.     

Cyclosporine,a P-glycoprotein modulator,increases [<Superscript>18</Superscript>F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

Purpose  Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[¹⁸F]fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF) for binding to hydroxytryptamine_1A (5-HT_1A) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Materials and methods  Each Sprague–Dawley rat (n = 4) received a baseline [¹⁸F]MPPF microPET scan followed by second scan 2–3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. Results  MicroPET studies showed that hippocampus uptake of [¹⁸F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [¹⁸F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. Conclusions  These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [¹⁸F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [¹⁸F]MPPF binding to 5-HT_1A receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT_1A receptor density when based on tracer uptake sensitive to P-gp modulation.     

Reliability of one-point blood sampling method for calculating input function in Na18F PET

OBJECTIVE: Conventional methods of quantitative Na18F positron emission tomography require multiple arterial blood sampling in order to obtain the input function, and the procedures are invasive and complicated. This study aims to establish a simplified and reliable technique for obtaining the input function. METHODS: Multiple arterial blood sampling was performed on 12 persons. The time point for one-point sampling was determined as the time when (1) the plasma radioactivity obtained showed the highest correlation to the real integrated value, which was calculated from the input function, and (2) the coefficient of variation of the real integrated value divided by plasma radioactivity obtained at each time point became the minimum. Scaling factors were obtained in order to estimate the plasma radioactivity at each time point, and a reference table was produced in order to estimate the input function. RESULTS: The optimal timing for one-point sampling was 12 min after intravenous injection of Na18F. The estimated integrated value obtained from arterial blood sampling at 12 min and the reference table was highly correlated with the real integrated value (P<0.001). Levels of plasma radioactivity of arterial blood and venous blood were almost the same at 12 and 40 min after Na18F injection. Percentage errors in the estimation of the integrated value were 2.63% (n=12) for the arterial blood collected at 12 min and 4.14% (n=12) for the venous blood collected at 30 min. CONCLUSIONS: This simplified method is clinically applicable and would replace traditional methods that require multiple blood sampling.     

Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study

Purpose The dopamine transporter (DAT) is a plasma membrane protein of central interest in the pathophysiology of neuropsychiatric disorders and is known to be a target for psychostimulant drugs. [¹¹C]PE2I is a new radioligand which binds selectively and with moderate affinity to central DAT, as has been demonstrated in vitro by autoradiography and in vivo by positron emission tomography (PET). The aims of the present PET study were to quantify regional [¹¹C]PE2I binding to DAT in the human brain and to compare quantitative methods with regard to suitability for applied clinical studies.Methods One PET measurement was performed in each of eight healthy male subjects. The binding potential (BP) values were obtained by applying kinetic compartment analysis, which uses the metabolite-corrected arterial plasma curve as an input function. They were compared with the BP values quantified by two reference tissue approaches, using cerebellum as a reference region representing free and non-specific radioligand binding.Results The radioactivity concentration was highest in the striatum, lower in the midbrain and very low in the cerebellum. The regional [¹¹C]PE2I binding could be interpreted by kinetic compartment models. However, the BP values in the striatum obtained by the compartment analyses were about 30% higher than the BP values obtained using reference tissue methods. We suggest that the difference may be explained by the inaccurate metabolite correction, small amounts of radioactive metabolites that could account for the presence of non-specific binding in the cerebellum and insufficient data acquisition time.Conclusion The reference methods may be used to quantify [¹¹C]PE2I binding in clinical studies, assuming that non-specific binding in the cerebellum does not vary between subjects and that an extended data acquisition time is employed. Moreover, the study corroborates the previous observation that [¹¹C]PE2I is advantageous for PET examination of DAT binding in the midbrain, a region from which dopaminergic innervation originates and which is of central interest for the pathophysiology of several neuropsychiatric disorders.     

Simplified reference region model for the kinetic analysis of [99mTc]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography

Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [^99mTc]TRODAT-1 in nonhuman primates, obviating the need for blood sampling. A series of dynamic SPET scans were performed on two baboons following the injection of approximately 700 MBq of [^99mTc]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reconstructed SPET images were co-registered with magnetic resonance imaging (MRI) scans of the baboons, and regions of interest (ROIs) placed on the striatum, cerebellum and cerebral hemispheres. The ROI data were combined with metabolite-corrected blood data, and fitted to a three-compartment kinetic model using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was derived from the nondisplaceable tissue compartment. In addition, semiquantitative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods generated values for the ratio of the kinetic rate constants k ₃ /k ₄, which gives an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k ₃ /k ₄ for the three different analysis techniques for each baboon were: 1.17±0.21 and 1.12±0.13 (full kinetic model), 0.93±0.13 and 0.90±0.07 (reference region model), and 0.97±0.18 and 0.92±0.08 (equilibrium method). The reference region method gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the kinetic data. The reference region model results for k ₃ /k ₄ correlated very strongly with the full kinetic analysis (r ² = 0.992, P<0.001), and with the equilibrium model (r ² = 0.88, P = 0.002). The subjectivity inherent in the equilibrium method produces inferior results compared with both kinetic analyses. It is suggested that the self-consistency of the reference region model, which requires no arterial blood sampling, provides a more precise and reliable estimate of the binding of [^99mTc]TRODAT-1 to dopamine transporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to distinguish smaller differences in dopaminergic function between patient groups. Received 26 October 1998 and in revised form 11 January 1999     

Quantitative analysis of dopamine transporters in human brain using [11C]PE2I and positron emission tomography: evaluation of reference tissue models

Objective

Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [¹¹C]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 [¹¹C]PE2I.

Methods

Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [¹¹C]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 [¹¹C]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 [¹¹C]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 [¹¹C]PE2I kinetics in the cerebellum and limited scan duration for ¹¹C, 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.     

Evaluation of the use of a standard input function for compartment analysis of [<Superscript>123</Superscript>I]iomazenil data: Factors influencing the quantitative results

Adoption of standard input function (SIF) has been proposed for kinetic analysis of receptor binding potential (BP), instead of invasive frequent arterial samplings. The purpose of this study was to assess the SIF method in quantitative analysis of [123I]iomazenil (IMZ), a central benzodiazepine antagonist, for SPECT. SPECT studies were performed on 10 patients with cerebrovascular disease or Alzheimer disease. Intermittent dynamic SPECT scans were performed from 0 to 201 min after IMZ-injection. BPs calculated from SIFs obtained from normal volunteers (BPs) were compared with those of individual arterial samplings (BPo). Good correlations were shown between BP(o)s and BP(s)s in the 9 subjects, but maximum BP(s)s were four times larger than the corresponding BP(o)s in one case. There were no abnormal laboratory data in this patient, but the relative arterial input count in the late period was higher than the SIF. Simulation studies with modified input functions revealed that height in the late period can produce significant errors in estimated BPs. These results suggested that the simplified method with one-point arterial sampling and SIF can not be applied clinically. One additional arterial sampling in the late period may be useful.