Physical and clinical performance of the mCT time-of-flight PET/CT scanner.

Time-of-flight (TOF) measurement capability promises to improve PET image quality. We characterized the physical and clinical PET performance of the first Biograph mCT TOF PET/CT scanner (Siemens Medical Solutions USA, Inc.) in comparison with its predecessor, the Biograph TruePoint TrueV. In particular, we defined the improvements with TOF. The physical performance was evaluated according to the National Electrical Manufacturers Association (NEMA) NU 2-2007 standard with additional measurements to specifically address the TOF capability. Patient data were analyzed to obtain the clinical performance of the scanner. As expected for the same size crystal detectors, a similar spatial resolution was measured on the mCT as on the TruePoint TrueV. The mCT demonstrated modestly higher sensitivity (increase by 19.7 ± 2.8%) and peak noise equivalent count rate (NECR) (increase by 15.5 ± 5.7%) with similar scatter fractions. The energy, time and spatial resolutions for a varying single count rate of up to 55 Mcps resulted in 11.5 ± 0.2% (FWHM), 527.5 ± 4.9 ps (FWHM) and 4.1 ± 0.0 mm (FWHM), respectively. With the addition of TOF, the mCT also produced substantially higher image contrast recovery and signal-to-noise ratios in a clinically-relevant phantom geometry. The benefits of TOF were clearly demonstrated in representative patient images.

A hybrid scatter correction for 3D PET based on an estimation of the distribution of unscattered coincidences: implementation on the ECAT EXACT HR+.

We implemented a hybrid scatter-correction method for 3D PET that combines two scatter-correction methods in a complementary way. The implemented scheme uses a method based on the discrimination of the energy of events (the estimation of trues method (ETM)) and an auxiliary method (the single scatter simulation method (SSSI) or the convolution-subtraction method (CONV)) in an attempt to increase the accuracy of the correction over a wider range of acquisitions. The ETM takes into account the scatter from outside the field-of-view (FOV), which is not estimated with the auxiliary method. On the other hand, the auxiliary method accounts for events that have scattered with small angles, which have an energy that cannot be discriminated from that of unscattered events using the ETM. The ETM uses the data acquired in an upper energy window above the photopeak (550-650 keV) to obtain a noisy estimate of the unscattered events in the standard window (350-650 keV). Our implementation uses the auxiliary method to correct the residual scatter in the upper window. After appropriate scaling, the upper window data are subtracted from the total coincidences acquired in the standard window, resulting in the final scatter estimate, after smoothing. In this work we compare the hybrid method with the corrections used by default in the 2D and 3D modes of the ECAT EXACT HR+ using phantom measurements. Generally, the contrast was better with the hybrid method, although the relative errors of quantification were similar. We conclude that hybrid techniques such as the one implemented in this work can provide an accurate, general-purpose and practical way to correct the scatter in 3D PET, taking into account the scatter from outside the FOV.

Iterative crystal efficiency calculation in fully 3-D PET.

The calculation of the intrinsic efficiency of individual crystals is one of the steps needed to obtain accurate images of the radioisotope distribution in positron emission tomography (PET). These efficiencies can be computed by comparing the number of coincidence counts obtained when the crystals are equally illuminated by the same source. However, because the number of coincidence counts acquired for one crystal also depends on the efficiency of the other crystals in coincidence, most methods of crystal efficiency calculation need to assume that the influence of the other crystals is negligible. If there are large crystal efficiency variations, this approximation may lead to systematic errors. We have recently implemented an iterative method for a single ring of detectors that does not rely on this assumption. In this paper, we describe a fully three-dimensional (3-D) iterative method that better exploits the sensitivity of the tomograph and allows reduced acquisition times or the use of narrow energy windows. We compare the performance of the iterative method (single-ring and extended to fully 3-D) with noniterative techniques for different acquisition times of a uniform cylinder. Two different energy windows were used to assess the performance of each method with different levels of variations of crystal efficiency. The results showed that the iterative methods are more accurate when large efficiency variations exist and that only the fully 3-D methods provided good efficiency estimates with very low duration scans. We, thus, conclude that iterative fully 3-D methods provide the best estimations and can be used in a larger range of situations than can the other methods tested.

Should scatter be corrected in both transmission and emission data for accurate quantitation in cardiac SPET?

Ideally, reliable quantitation in single-photon emission tomography (SPET) requires both emission and transmission data to be scatter free. Although scatter in emission data has been extensively studied, it is not well known how scatter in transmission data affects relative and absolute quantitation in reconstructed images. We studied SPET quantitative accuracy for different amounts of scatter in emission and transmission data using a Utah phantom and a cardiac Data Spectrum phantom including different attenuating media. Acquisitions over 180 degrees were considered and three projection sets were derived: 20% images and Jaszczak and triple-energy-window scatter-corrected projections. Transmission data were acquired using gadolinium-153 line sources in a 90-110 keV window using a narrow or wide scanning window. The transmission scans were performed either simultaneously with the emission acquisition or 24 h later. Transmission maps were reconstructed using filtered backprojection and mu values were linearly scaled from 100 to 140 keV. Attenuation-corrected images were reconstructed using a conjugate gradient minimal residual algorithm. The mu value underestimation varied between 4% with a narrow transmission window in soft tissue and 22% with a wide window in a material simulating bone. Scatter in the emission and transmission data had little effect on the uniformity of activity distribution in the left ventricle wall and in a uniformly hot compartment of the Utah phantom. Correcting the transmission data for scatter had no impact on contrast between a hot and a cold region or on signal-to-noise ratio (SNR) in regions with uniform activity distribution, while correcting the emission data for scatter improved contrast and reduced SNR. For absolute quantitation, the most accurate results (bias <4% in both phantoms) were obtained when reducing scatter in both emission and transmission data. In conclusion, trying to obtain the same amount of scatter in emission and transmission data, in addition to being impractical because of the difficulty in knowing the precise scatter components, did not yield such accurate absolute activity quantitation as when emission and transmission scatter were reduced.

Comparison of clinical data sets acquired on different tomographs using 6-18F-L-dopa.

Longitudinal positron emission tomography (PET) studies of 6-18F-L-dopa uptake in the striatum are used to assess the progression of Parkinson's disease or the survival of neuronal cells grafted in parkinsonian patients. These studies are performed over several years, and data analysis may suffer from the change from old tomographs to new machines with better sensitivity and spatial resolution. Furthermore, such studies on parkinsonian patients may be accomplished in either 2D or 3D acquisition mode. The aforementioned improvements offer great benefits for the study of neurodegenerative diseases, especially those affecting the striatum. However, direct comparison of data is not straightforward owing to variation in scanner characteristics. In this study, we assessed the feasibility of comparing the 6-18F-L-dopa striatal uptake values (Kc) measured in two groups of healthy subjects using two tomographs of different generations. We re-studied and compared acquisitions performed on 14 healthy subjects using 6-18F-L-dopa. Half of these studies had been performed in 2D acquisition mode using an ECAT 953B. The other half had been performed in 3D acquisition mode using an ECAT EXACT HR+. Different reconstruction protocols were used and the Kc values obtained were statistically compared. The results showed that lowering the transverse spatial resolution of images obtained with the scanner having the better spatial resolution, so that it more closely matched that of the other machine, allowed similar KC values to be obtained in healthy subjects. This study shows that quantitative results of 6-18F-L-dopa scans can be matched between different scanners with different intrinsic resolutions. This can be accomplished using adequate modifications of the reconstruction parameters. Such modifications can be used to help in the longitudinal monitoring of parkinsonian patients using different tomographs.

Comparison of fluorine-18 and bromine-76 imaging in positron emission tomography.

State of the art positron emission tomography (PET) systems allow for scatter and attenuation correction. However, the size of the structure being studied and the region of interest (ROI) chosen also influence the accuracy of measurements of radioactive concentration. Furthermore, the limited spatial resolution of PET tomographs, which depends, among other factors, on the range of positrons in matter, can also contribute to a loss in quantitation accuracy. In this paper we address the influence of positron range, structure size and ROI size on the quantitation of radioactive concentration using PET. ECAT EXACT HR+ (HR+) and ECAT 953B/31 (ECAT 953B) PET systems were used in phantom acquisitions performed with two radioisotopes with different positron ranges. The 3D Hoffman phantom was scanned on both scanners with both radioisotopes, to visually analyse the image quality. A resolution phantom having six spheres of different diameters in a Plexiglas cylinder was used to calculate the values of the contrast recovery coefficient or hot spot recovery coefficient and of the spill-over or cold spot recovery coefficient under different imaging conditions used in clinical routine at our institution. Activity ratios were varied between 2 and 30 or between 0.4 and 200 by filling the spheres with fluorine-18 or bromine-76 respectively and the cylinder with 11C. Dynamic scans were performed on each scanner. Data were reconstructed using the same parameters as are used in clinical protocols. The variations in sphere and cylinder activities with time were fitted using the function M(t)=k1. A(t)+k2.B(t), where M(t) is the radioactivity concentration measured in an ROI placed on each sphere and A(t) and B(t) represent the true radioactivity concentrations present at time t in the spheres and in the cylinder respectively. k1 and k2 are factors representing the contrast recovery coefficient and the spill-over from surrounding activity on measurements respectively. The visual analysis of images obtained using a 3D Hoffman phantom showed that image resolution and image contrast between different regions are radioisotope dependent and clearly better when using 18F. Linear profiles taken on these images confirmed the visual assessment. For a given scanner, the k1 values obtained with 18F were systematically higher than those measured using 76Br in the same machine (especially for the smaller spheres) when using the same ROI. For a sphere of a particular diameter, the use of a wider ROI resulted in lower quantitative accuracy when using the same isotope and the same camera. Lower quantitative accuracy was found for smaller spheres for all ROI sizes used in image analysis. For the same scanner and for a similar imaging situation (same sphere and same ROI), it was found that k1 and k2 values depend on the radioisotope used. For the same isotope and tomograph, the k1 values obtained decreased with the size of the structures imaged, as well as with the increase in ROI size. The use of a tomograph with better spatial resolution (HR+, rather than ECAT 953B) greatly increased the k1 values for 18F while only a mild improvement in these values was observed for 76Br. The use of 76Br led to k2 values that were slightly higher than those measured using 18F. These differences may have been due to the difference in the range of the positrons emitted by the radioisotopes used in this study. The measurements performed in this study show that the comparison of studies obtained on the same camera depends on the radioisotope used and may require the adaptation of ROI size between examinations. Marked differences are visible if the positron ranges of such radioisotopes are very different. Therefore, when employing commercially available tomographs and imaging protocols used in clinical routine, the effects of differences in positron range on image quality and quantitation are noticeable and correction for these effects may be of importance. (ABSTRACT TRUNCATED)

Respective roles of scatter, attenuation, depth-dependent collimator response and finite spatial resolution in cardiac single-photon emission tomography quantitation: a Monte Carlo study.

The purpose of this study was to investigate the relative influence of scatter, attenuation, depth-dependent collimator response and finite spatial resolution upon the image characteristics in cardiac single-photon emission tomography (SPET). An acquisition of an anthropomorphic cardiac phantom was performed together with corresponding SPET Monte Carlo simulations. The cardiac phantom and the Monte Carlo simulations were designed so that the effect of scatter, attenuation, depth-dependent collimator response and finite spatial resolution could be studied individually and in combination. The impact of each physical effect and of combinations of effects was studied in terms of absolute and relative quantitative accuracy, spatial resolution and signal-to-noise ratio (SNR) in the resulting images. No corrections for these effects were assessed. Results obtained from Monte Carlo simulations and real acquisitions were in excellent agreement. Attenuation introduced about 90% activity underestimation in a 10-mm-thick left ventricle wall while finite spatial resolution alone introduced about 30% activity underestimation. Scatter had a negligible impact on quantitative accuracy in the recontructed slices when attenuation was present. Neither bull's eye map homogeneity nor contrast between a hot and a cold region were affected by depth-dependent collimator response or finite spatial resolution. Bull's eye map homogeneity was severely affected by attenuation but not by scatter. Attenuation and scatter reduced contrast by about 20% each. Both attenuation and scatter increased the full-width at half-maximum (FWHM) characterizing the spatial resolution of the imaging system by approximately 1 mm each but the main effect responsible for the observed 11-mm FWHM spatial resolution was the depth-dependent collimator response. SNR was reduced by a factor of approximately 2.5 because of attenuation, while scattered counts increased SNR by approximately 10%. In conclusion, the quantification of the relative influence of the different physical effects showed that attenuation is definitely the major phenomenon affecting cardiac SPET imaging accuracy, but that finite spatial resolution, scatter and depth-dependent collimator response also contribute significantly to the errors in absolute and relative quantitation and to the poor spatial resolution.

Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach.

The multi-injection approach has been used to study in baboon the in vivo interactions between the D2 receptor sites and FLB 457, a ligand with a very high affinity for these receptors. The model structure was composed of four compartments (plasma, free ligand, and specifically and unspecifically bound ligands) and seven parameters (including the D2 receptor site density). The arterial plasma concentration, after correction for metabolites, was used as the input function. The experimental protocol, which consisted of three injections of labeled and/or unlabeled ligand, allowed the evaluation of all model parameters from a single positron emission tomography experiment. In particular, the concentration of receptor sites available for binding (B'max) and the apparent in vivo FLB 457 affinity were estimated in seven brain regions, including the cerebellum and several cortex regions, in which these parameters are estimated in vivo for the first time (B'max is estimated to be 4.0+/-1.3 pmol/mL in the thalamus and from 0.32 to 1.90 pmol/mL in the cortex). A low receptor density was found in the cerebellum (B'max = 0.39+/-0.17 pmol/mL), whereas the cerebellum is usually used as a reference region assumed to be devoid of D2 receptor sites. In spite of this very small concentration (1% of the striatal concentration), and because of the high affinity of the ligand, we demonstrated that after a tracer injection, most of the PET-measured radioactivity in the cerebellum results from the labeled ligand bound to receptor sites. The estimation of all the model parameters allowed simulations that led to a precise knowledge of the FLB 457 kinetics in all brain regions and gave the possibility of testing the equilibrium hypotheses and estimating the biases introduced by the usual simplified approaches.

Robustness of anatomically guided pixel-by-pixel algorithms for partial volume effect correction in positron emission tomography.

Several algorithms have been proposed to improve positron emission tomography quantification by combining anatomical and functional information in a pixel-by-pixel correction scheme. The precision of these methods when applied to real data depends on the precision of the manifold correction steps, such as full-width half-maximum modeling, magnetic resonance imaging-positron emission tomography registration, tissue segmentation, or background activity estimation. A good understanding of the influence of these parameters thus is critical to the effective use of the algorithms. In the current article, the authors present a monodimensional model that allows a simple theoretical and experimental evaluation of correction imprecision. The authors then assess correction robustness in three dimensions with computer simulations, and evaluate the validity of regional SD as a correction performance criterion.

Absolute quantitation of iodine-123 epidepride kinetics using single-photon emission tomography: comparison with carbon-11 epidepride and positron emission tomography.

Epidepride labelled with iodine-123 is a suitable probe for the in vivo imaging of striatal and extrastriatal dopamine D2 receptors using single-photon emission tomography (SPET). Recently, this molecule has also been labelled with carbon-11. The goal of this work was to develop a method allowing the in vivo quantification of radioactivity uptake in baboon brain using SPET and to validate it using positron emission tomography (PET). SPET studies were performed in Papio anubis baboons using 123I-epidepride. Emission and transmission measurements were acquired on a dual-headed system with variable head angulation and low-energy ultra-high resolution (LEUHR) collimation. The imaging protocol consisted of one transmission measurement (24 min, heads at 90 degrees), obtained with two sliding line sources of gadolinium-153 prior to injection of 0.21-0.46 GBq of 123I-epidepride, and 12 emission measurements starting 5 min post injection. For scatter correction (SC) we used a dual-window method adapted to 123I. Collimator blurring correction (CBC) was done by deconvolution in Fourier space and attenuation correction (AT) was applied on a preliminary (CBC) filtered back-projection reconstruction using 12 iterations of a preconditioned, regularized minimal residual algorithm. For each reconstruction, a calibration factor was derived from a uniform cylinder filled with a 123I solution of a known radioactivity concentration. Calibration and baboon images were systematically built with the same reconstruction parameters. Uncorrected (UNC) and (AT), (SC + AT) and (SC + CBC + AT) corrected images were compared. PET acquisitions using 0.11-0.44 GBq of 11C-epidepride were performed on the same baboons and used as a reference. The radioactive concentrations expressed in percent of the injected dose per 100 ml (% ID/100 ml) obtained after (SC + CBC + AT) in SPET are in good agreement with those obtained with PET and 11C-epidepride. A method for the in vivo absolute quantitation of 123I-epidepride uptake using SPET has been developed which can be directly applied to other 123I-labelled molecules used in the study of the dopamine system. Further work will consist in using PET to model the radioligand-receptor interactions and to derive a simplified model applicable in SPET.

Dosimetry of transmission measurements in nuclear medicine: a study using anthropomorphic phantoms and thermoluminescent dosimeters.

Quantification in positron emission tomography (PET) and single photon emission tomographic (SPET) relies on attenuation correction which is generally obtained with an additional transmission measurement. Therefore, the evaluation of the radiation doses received by patients needs to include the contribution of transmission procedures in SPET (SPET-TM) and PET (PET-TM). In this work we have measured these doses for both PET-TM and SPET-TM. PET-TM was performed on an ECAT EXACT HR+ (CTI/Siemens) equipped with three rod sources of germanium-68 (380 MBq total) and extended septa. SPET-TM was performed on a DST (SMV) equipped with two collimated line sources of gadolinium-153 (4 GBq total). Two anthropomorphic phantoms representing a human head and a human torso, were used to estimate the doses absorbed in typical cardiac and brain transmission studies. Measurements were made with thermoluminescent dosimeters (TLDs, consisting of lithium fluoride) having characteristics suitable for dosimetry investigations in nuclear medicine. Sets of TLDs were placed inside small plastic bags and then attached to different organs of the phantoms (at least two TLDs were assigned to a given organ). Before and after irradiation the TLDs were placed in a 2.5-cm-thick lead container to prevent exposure from occasional sources. Ambient radiation was monitored and taken into account in calculations. Transmission scans were performed for more than 12 h in each case to decrease statistical noise fluctuations. The doses absorbed by each organ were calculated by averaging the values obtained for each corresponding TLD. These values were used to evaluate the effective dose (ED) following guidelines described in ICRP report number 60. The estimated ED values for cardiac acquisitions were 7.7 x 10(-4) +/- 0.4 x 10(-4) mSv/MBq.h and 1.9 x 10(-6) +/- 0.4 x 10(-6) mSv/MBq.h for PET-TM and SPET-TM, respectively. For brain scans, the values of ED were calculated as 2.7 x 10(-4) +/- 0.2 x 10(-4) mSv/MBq.h for PET-TM and 5.2 x 10(-7) +/- 2.3 x 10(-7) mSv/MBq.h for SPET-TM. In our institution, PET-TM is usually performed for 15 min prior to emission. SPET-TM is performed simultaneously with emission and usually lasts 30 and 15 min for brain and cardiac acquisitions respectively. Under these conditions ED values, estimated for typical source activities at delivery time (22,000 MBq in SPET and 555 MBq for PET), were 1.1 x 10(-1) +/- 0.1 x 10(-1) mSv and 1.1 x 10(-2) +/- 0.2 x 10(-2) mSv for cardiac PET-TM and SPET-TM respectively. For brain acquisitions, the ED values obtained under the same conditions were 3.7 x 10(-2) +/- 0.3 x 10(-2) mSv and 5.8 x 10(-3) +/- 2.6 x 10(-3) mSv for PET-TM and SPET-TM respectively. These measurements show that the dose received by a patient during a transmission scan adds little to the typical dose received in a routine nuclear medicine procedure. Radiation dose, therefore, does not represent a limit to the generalised use of transmission measurements in clinical SPET or PET.

[Fluorodeoxyglucose and bronchopulmonary cancer. Initial French results with positron emission tomography]. / Fluoro-déoxy-glucose et cancer bronchopulmonaire. Les premiers résultats français en caméra à positons.

Despite recent advances, the contribution of medical imaging techniques is limited, particularly in terms of tissue characterization, in the diagnosis of pulmonary nodules and search for extension of bronchogenic cancer. The metabolic properties of the glucose analog deoxyglucose labeled with 18F1 would allow metabolic imaging. Positron emission tomography (PET) provides clinicians with quality images with an interesting sensitivity. We report the results of a feasibility study conducted in our first 17 patients. We observed 14 true positives, 1 true negative and 1 false positive and 1 false negative in patients with a malignant primary lesion. We analyzed the causes of error. Ten disseminated localizations were identified. Possible developments in terms of therapeutic strategy are discussed. The agreement between our findings and data reported in the literature prompted us to develop a study protocol using 18-fluorodeoxyglucose PET in patients with bronchogenic cancer.

Validation of the three-dimensional acquisition mode in positron emission tomography for the quantitation of [18F]fluoro-DOPA uptake in the human striata.

Three-dimensional (3D) positron emission tomography (PET) is attractive for [18F]fluoro-DOPA studies, since the sensitivity improvement is maximal for radioactive sources located in central planes, which is usually the case for the human striata. However, the image quantitation in that mode must be assessed because of the nearly threefold increase in scattered coincidences. We report the results of [18F]fluoro-DOPA studies performed on six normal volunteers. Each one was scanned in the 3D and two-dimensional (2D) modes on the same tomograph. The quantitation in the 3D and 2D modes was compared for a Patlak graphical analysis with the occipital counts as the input function (Ki) and a striatooccipital ratio analysis. We find that, in 3D PET, a scatter correction is required to preserve the same quantitation as in 2D PET. When the 3D data sets are corrected for scatter, the quantitation of the [18F]fluoro-DOPA uptake, using the Patlak analysis, is similar in the 2D and 3D acquisition modes. Conversely, analysis of the striatooccipital ratio leads to higher values in 3D PET because of a better in-plane resolution. Finally, using the 3D mode, the dose injected to the subjects can be reduced by a factor greater than 1.5 without any loss in accuracy compared to the 2D mode.

Parametric images of benzodiazepine receptor concentration using a partial-saturation injection.

The in vivo quantification of the benzodiazepine receptor concentration in human brain using positron emission tomography (PET) and 11C-flumazenil (11C-FMZ), is usually based on a three-compartment model and on PET curves measured in a small number of large regions of interest; however, it should be interesting to estimate the receptor concentration for each pixel and to build quantified images of the receptor concentration. The main advantage is to allow screening of the receptor site localization and visual observation of the possible abnormalities. Up to now, all the methods described include complex experimental protocols, difficult to use in routine examinations. In this paper, we propose the partial-saturation approach to obtain parametric images of benzodiazepine receptor concentration and FMZ affinity. It consists of a single FMZ injection with a low specific activity, followed by Scatchard analysis. Like other parametric imaging methods, this partial-saturation approach can lead to a small percentage (< 1%) of unrealistic values in receptor-poor regions; however, it is the only method that allows receptor concentration and affinity images to be obtained from a single-injection 40-min experiment without blood sampling. We also propose a second method in which the receptor concentration map is directly deduced from the PET image acquired 5 to 10 min after a partial-saturation injection. This method assumes a known and constant FMZ affinity value but requires only very simple corrections of this PET image. It is robust (negative values are never found) and quite simple to use in routine examination of patients (no blood sampling, single injection, only 10-min experiment).

Quantitative imaging of iodine-124 with PET.

UNLABELLED: PET is potentially very useful for the accurate in vivo quantitation of time-varying biological distributions of radiolabeled antibodies over several days. The short half-lives of most commonly used positron-emitting nuclides make them unsuitable for this purpose. Iodine-124 is a positron emitter with a half-life of 4.2 days and appropriate chemical properties. It has not been widely used because of a complex decay scheme including several high energy gamma rays. However, measurements made under realistic conditions on several different PET scanners have shown that satisfactory imaging and quantitation can be achieved. METHODS: Whole-body and head-optimized scanners with different detectors (discrete BGO, block BGO and BaF2 time-of-flight), different septa and different correction schemes were used. Measurements of resolution, quantitative linearity and the ability to quantitatively image spheres of different sizes and activities in different background activities were made using phantoms. RESULTS: Compared with conventional PET nuclides, resolution and quantitation were only slightly degraded. Sphere detectability was also only slightly worse if imaging time was increased to compensate for the lower positron abundance. CONCLUSION: Quantitative imaging with 124I appears to be possible under realistic conditions with various PET scanners.

Concept of reaction volume in the in vivo ligand-receptor model.

UNLABELLED: In vivo quantification of receptor concentration and ligand affinity using data obtained with PET is based on the compartmental analysis of ligand-receptor interactions. There is, however, an inconsistency between the assumed homogeneity of the ligand concentration in each compartment, a basic hypothesis of the compartmental analysis, and the obvious heterogeneity of the tissue. Our goal was to study the effects of the free ligand concentration heterogeneity on the parameters describing in vivo binding reaction and to introduce the concept of reaction volume, VR, to account for that heterogeneity. METHODS: The reaction volume is defined as the volume in which the free ligand mass present in 1 ml of tissue would have uniformly distributed with the same concentration as that in the vicinity of the receptor sites. The consequence of the heterogeneity of the free ligand concentration is that the equilibrium dissociation rate constant estimated from PET data corresponds to KdVR and not to Kd alone (defined by the ratio of the dissociation over the association rate constants). As a consequence, it is proposed to estimate the reaction volume as the ratio between the equilibrium dissociation constants obtained from in vivo and in vitro data (KdVR and Kd, respectively). RESULTS: We used data obtained from studies performed with eight different molecules and found a correlation between the reaction volume and the molecule lipophilicity. This correlation can be used as a method to estimate the order of magnitude of VR from the lipophilicity which is easily accessible experimentally. CONCLUSION: Reaction volume is an important parameter in in vivo ligand-receptor interaction modeling.

Quantitation of benzodiazepine receptors in human brain using the partial saturation method.

UNLABELLED: The in vivo quantification of the benzodiazepine receptor concentration in humans using PET and flumazenil (FMZ) is usually based on Scatchard analysis when the goal is to avoid blood sampling. The experimental protocols, however, include several (at least two) experiments with various specific activities in the same subject to obtain a range of bound ligand concentrations. METHODS: We propose the partial saturation method, which is based on a natural decrease in bound ligand concentration after an FMZ injection with an average dose between a tracer dose and a saturation dose. An adequate range of bound ligand concentrations can thus be obtained from a single experiment. The free ligand concentration is estimated from the PET measurement in the pons after correction for the effect of the small receptor site concentration in this reference region. RESULTS: The receptor concentration and affinity estimates obtained with this approach in six regions of interest agree with previously published values obtained by using more complex approaches. Receptor concentration appears to be insensitive to the uncertainties with regard to the receptor site concentration in the pons. CONCLUSION: The partial saturation protocol can be used to estimate both the benzodiazepine receptor concentration and the FMZ affinity in routine examinations in adults (or even in children) using a single 40-min experiment without blood sampling.

Parameter and index images of benzodiazepine receptor concentration in the brain.

UNLABELLED: In vivo studies of ligand-receptor interactions with PET data are based on different approaches that provide either quantitative results (receptor density and affinity) or indices that are assumed to be correlated with the receptor concentration. The aims of this study are to obtain parametric images of benzodiazepine receptor concentration and of flumazenil affinity and to study the validity of two receptor concentration indexes. METHODS: A three-compartment ligand-receptor model, [11C]flumazenil, and experimental data obtained using a three-injection protocol in human volunteers were used to acquire parametric images. The delayed activity method and the apparent distribution volume (estimated using a two-compartment model) were also tested and their results compared with those of the multi-injection approach. RESULTS: Parametric images of receptor density, affinity and all kinetic parameters were obtained with acceptable variation coefficients. A correlation between receptor density and apparent affinity was found (r = 0.83; p < 0.0005). The correlation between receptor concentration and apparent distribution volume (estimated with three- and two-compartment models, respectively) was accessed using both a linear (the usual hypothesis) and a nonlinear correlation derived from the relationship between the receptor density and the affinity. CONCLUSION: In spite of the complexity of this protocol (three injections, a 2-hr experiment, blood sampling and a metabolite study), we showed that the multi-injection approach is suitable for parametric brain imaging. By using this approach as a reference, we deduced that the distribution volume and delayed activity images are valid methods in the usual range of the benzodiazepine receptor concentrations found in the human brain.