Animal Positron Emission Tomography System Research Articles

Setup and characterisation according to NEMA NU 4 of the phenoPET scanner, a PET system dedicated for plant sciences

Objective. The phenoPET system is a plant dedicated positron emission tomography (PET) scanner consisting of fully digital photo multipliers with lutetium–yttrium oxyorthosilicate crystals and located inside a custom climate chamber. Here, we present the setup of phenoPET, its data processing and image reconstruction together with its performance. Approach. The performance characterization follows the national electrical manufacturers association (NEMA) standard for small animal PET systems with a number of adoptions due to the vertical oriented bore of a PET for plant sciences. In addition temperature stability and spatial resolution with a hot rod phantom are addressed. Main results. The spatial resolution for a 22Na point source at a radial distance of 5 mm to the center of the field-of-view (FOV) is 1.45 mm, 0.82 mm and 1.88 mm with filtered back projection in radial, tangential and axial direction, respectively. A hot rod phantom with 18F gives a spatial resolution of up to 1.6 mm. The peak noise-equivalent count rates are 550 kcps @ 35.08 MBq, 308 kcps @ 33 MBq and 45 kcps @ 40.60 MBq for the mouse, rat and monkey size scatter phantoms, respectively. The scatter fractions for these phantoms are 12.63%, 22.64% and 55.90%. We observe a peak sensitivity of up to 3.6% and a total sensitivity of up to S A,tot = 2.17%. For the NEMA image quality phantom we observe a uniformity of %STD = 4.22% with ordinary Poisson maximum likelihood expectation-maximization with 52 iterations. Here, recovery coefficients of 0.12, 0.64, 0.89, 0.93 and 0.91 for 1 mm, 2 mm, 3 mm, 4 mm and 5 mm rods are obtained and spill-over ratios of 0.08 and 0.14 for the water-filled and air-filled inserts, respectively. Significance. The phenoPET and its laboratory are now in routine operation for the administration of [11C]CO2 and non-invasive measurement of transport and allocation of 11C-labelled photoassimilates in plants.

Background reduction in PET by double Compton scattering of quantum entangled annihilation photons

The reduction of background events, such as random and scatter events, can improve positron emission tomography (PET) images quantitatively. The quantum entanglement property of annihilation photons has been theoretically studied and experimentally validated. Recently, simulation studies on PET image reconstruction using the quantum entanglement property of annihilation photons and studies on the measurement of entanglement and polarization properties with scintillation crystal arrays demonstrated that PET images with less background can be achieved. This study utilized the quantum entanglement property of annihilation photons in a typical PET system with block detectors. A data acquisition method for quantum entanglement PET (QEPET) and system response modelling for QEPET image reconstruction were proposed and implemented. An experimental study was conducted using a small animal PET system composed of Ce:GAGG scintillation crystals whose dimensions are 2.5 × 2.5 × 4mm3. The diameter of the system was 79.3 mm. Signals from all individual crystals were processed parallelly and independently; thus, Compton scatter and absorption crystals within a module were obtained directly. The 28 MBq experiment result revealed the random background ratio of QEPET was approximately 20% lower than that of PET and the count rate of QEPET was approximately 0.1% that of PET. Evaluation on reconstructed images from the 28 MBq experiment revealed that the signal-to-background ratio of QEPET was approximately two times better than that of PET while the signal-to-noise ratio of QEPET was about 77% of that of PET. The method proposed in this study is expected to improve PET images with high background, such as those with a high activity and high background gamma rays and improve range verification in proton therapy.

A CNN-based four-layer DOI encoding detector using LYSO and BGO scintillators for small animal PET imaging

Objective. We propose a novel four-layer depth-of-interaction (DOI) encoding phoswich detector using lutetium–yttrium oxyothosilicate (LYSO) and bismuth germanate (BGO) scintillator crystal arrays for high sensitivity and high spatial resolution small animal PET imaging. Approach. The detector was comprised of a stack of four alternating LYSO and BGO scintillator crystal arrays coupled to an 8 × 8 multi-pixel photon counter (MPPC) array and read out by a PETsys TOFPET2 application specific integrated circuit. The four layers from the top (gamma ray entrance) to the bottom (facing the MPPC) consisted of a 24 × 24 array of 0.99 × 0.99 × 6 mm3 LYSO crystals, a 24 × 24 array of 0.99 × 0.99 × 6 mm3 BGO crystals, a 16 × 16 array of 1.53 × 1.53 × 6 mm3 LYSO crystals and a 16 × 16 array of 1.53 × 1.53 × 6 mm3 BGO crystals. Main results. Events that occurred in the LYSO and BGO layers were first separated by measuring the pulse energy (integrated charge) and duration (time over threshold (ToT)) from the scintillation pulses. Convolutional neural networks (CNNs) were then used to distinguish between the top and lower LYSO layers and between the upper and bottom BGO layers. Measurements with the prototype detector showed that our proposed method successfully identified events from all four layers. The CNN models achieved a classification accuracy of 91% for distinguishing the two LYSO layers and 81% for distinguishing the two BGO layers. The measured average energy resolution was 13.1% ± 1.7% for the top LYSO layer, 34.0% ± 6.3% for the upper BGO layer, 12.3% ± 1.3% for the lower LYSO layer, and 33.9% ± 6.9% for the bottom BGO layer. The timing resolution between each individual layer (from the top to the bottom) and a single crystal reference detector was 350 ps, 2.8 ns, 328 ps, and 2.1 ns respectively. Significance. In conclusion, the proposed four-layer DOI encoding detector achieved high performance and is an attractive choice for next-generation high sensitivity and high spatial resolution small animal positron emission tomography systems.

Development of dual-ended depth-of-interaction detectors using laser-induced crystals for small animal PET systems

Sensitivity and spatial resolution of positron emission tomography (PET) scanners can be improved by using thicker scintillation crystals with depth-of-interaction (DOI) encoding. Subsurface laser engraving (SSLE) can be used to segment crystals of a scintillation detector in order to fabricate a DOI detector. We previously applied SSLE to crystal bars of 3 × 3 × 20 mm3 and 1.5 × 1.5 × 20 mm3 and developed two dual-ended detectors with DOI segments of 3 mm and 1.5 mm, respectively. To further improve the DOI resolution, our SSLE detector design can be used with smaller pitch crystal bars, making them excellent detector candidates for small animal PET scanners with submillimetre resolution. In the present study, three small crystal bars of 1 × 1 × 20 mm3, 2 × 1 × 20 mm3, and 2 × 1 × 40 mm3 were laser engraved to 12, 20 and 40 segments, respectively, by applying SSLE in their height directions. The segmented crystal bars were characterised in three prototype detector arrangements. First, the 1 × 1 × 20 mm3 crystal bars were characterised in an 8 × 8 crystal array designed for DOI encoding along crystal height in a conventional small animal PET design. Second, a 4 × 8 crystal array of 2 × 1 × 20 mm3 crystal bars was characterised for using the DOI information for crystal interaction positioning along the axial axis of a small animal PET scanner. Finally, the third part of the study was performed on a single 2 × 1 × 40 mm3 crystal bar with 40 segments to investigate the feasibility of DOI estimation in longer crystals for application in a system with extended axial length. We evaluated the capability of segment identification and energy resolution of theses detectors. The 3D position maps of the detectors were obtained using the Anger-type calculation and the crystal identification performance was evaluated for each detector. Clear segment separation was obtained for the crystal arrays with 12 (segment pitch of 1.67 mm) and 20 (segment pitch of 1 mm) segments. Mean energy resolutions of 8.8% ± 0.4% and 9.6% ± 0.8% at 511 keV were obtained for the segments in the central regions of the 8 × 8 array with 12 segments and the 4 × 8 array with 20 segments, respectively. Clear segment identification was found to be difficult for the detector with 40 segments, especially for the segments at the middle of the crystal. Energy and interaction positioning characterisation results suggest that both prototype detectors with 12 and 20 segments are well suited for small animal PET scanners with high spatial resolution.

18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species

Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n = 1), rats (n = 4), rabbits (n = 4) and non-human primates (n = 3), via carotid artery in rats (n = 4) and non-human primates (n = 3), and via intra-myocardial injection in rats (n = 5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.

The Number of Frames on ECG-Gated 18F-FDG Small Animal PET Has a Significant Impact on LV Systolic and Diastolic Functional Parameters.

Objectives This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods 18F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 ± 57.7 μl∗, 380.8 ± 57.2 μl∗, 398.0 ± 63.1 μl∗, and 444.8 ± 75.3 μl at 4, 8, 12, and 16 frames, respectively; ∗P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames. Conclusions Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.

Robust Detector Calibration for a Novel PET System Based on Cross-Strip CZT Detectors

In positron emission tomography (PET) imaging, high energy and spatial resolution are necessary to obtain high quality images. This paper presents a photon interaction position dependent energy calibration for a small animal PET system built with cadmium zinc telluride (CZT) crystals. 3-D-resolving CZT detection systems employ up to 103–105 read-out channels which require individual calibration due to position-varying crystal quality. This paper aims to establish an automated data processing algorithm to minimize manual intervention and guarantee consistent calibration. The algorithm analyzes the data using a two-step process with a calibration and validation step. The validation step is a spectrum analysis which utilizes a non- Gaussian shape function. The calibration step is a position dependent photopeak recovery where three different methods were studied. The analysis of the uncorrected data reveals an energy resolution of (8.4%±0.2%) FWHM at 511 keV. The best performance is achieved with the proposed processing, which yields an energy resolution of (7.0%±0.1%) FWHM at 511 keV. The robustness of the shape function used to determine the energy resolution was evaluated and was found to be superior compared to a pure Gaussian shape function. In summary, the proposed data algorithm can generate calibration parameters in a robust manner and provides a consistent calibration.

Crystal identification for a dual-layer-offset LYSO based PET system via Lu-176 background radiation and mean shift algorithm

Modern positron emission tomography (PET) detectors are made from pixelated scintillation crystal arrays and readout by Anger logic. The interaction position of the gamma-ray should be assigned to a crystal using a crystal position map or look-up table. Crystal identification is a critical procedure for pixelated PET systems. In this paper, we propose a novel crystal identification method for a dual-layer-offset LYSO based animal PET system via Lu-176 background radiation and mean shift algorithm. Single photon event data of the Lu-176 background radiation are acquired in list-mode for 3 h to generate a single photon flood map (SPFM). Coincidence events are obtained from the same data using time information to generate a coincidence flood map (CFM). The CFM is used to identify the peaks of the inner layer using the mean shift algorithm. The response of the inner layer is deducted from the SPFM by subtracting CFM. Then, the peaks of the outer layer are also identified using the mean shift algorithm. The automatically identified peaks are manually inspected by a graphical user interface program. Finally, a crystal position map is generated using a distance criterion based on these peaks. The proposed method is verified on the animal PET system with 48 detector blocks on a laptop with an Intel i7-5500U processor. The total runtime for whole system peak identification is 67.9 s. Results show that the automatic crystal identification has 99.98% and 99.09% accuracy for the peaks of the inner and outer layers of the whole system respectively. In conclusion, the proposed method is suitable for the dual-layer-offset lutetium based PET system to perform crystal identification instead of external radiation sources.

New-generation small animal positron emission tomography system for molecular imaging.

The next generation of discoveries in molecular imaging requires positron emission tomography (PET) systems with high spatial resolution and high sensitivity to visualize and quantify low concentrations of molecular probes. The goal of this work is to assemble and explore such a system. We use cadmium zinc telluride (CZT) to achieve high spatial resolution, three-dimensional interaction positioning, and excellent energy resolution. The CZT crystals are arranged in an edge-on configuration with a minimum gap of [Formula: see text] in a four-sided panel geometry to achieve superior photon sensitivity. The developed CZT detectors and readout electronics were scaled up to complete significant portions of the final PET system. The steering electrode bias and the amplitude of the analog signals for time measurement were optimized to improve performance. The energy resolution (at 511keV) over 468 channels is [Formula: see text] full-width-at-half-maximum (FWHM). The spatial resolution is [Formula: see text] FWHM. The time resolution of six CZT crystals in coincidence with six other CZT crystals is 37ns. With high energy and spatial resolution and the relatively low random rate for small animal imaging, this system shows promise to be very useful for molecular imaging studies.

Impact of tissue photon attenuation in small animal cardiac PET imaging

ObjectivesTissue photon attenuation is one of the essential artifacts requiring correction in clinical cardiac positron emission tomography (PET) imaging. However, due to small body size its impact on diagnostic accuracy in small rodents is considered to be limited or even ignorable. The present cardiac PET study compares lean and obese rats to determine the influence of tissue attenuation on quantitative assessment as well as regional tracer distribution. MethodsA dedicated small animal PET system equipped with a 57Co rotating source for transmission was used. To assess the impact of tissue attenuation in rats with different body sizes, cardiac 18F­FDG -PET studies for Zucker diabetic fatty rats (obese rats) and Zucker lean rats (lean rats) were performed. The radiotracer activity reduction by attenuation was compared between the two groups. Regional tracer distribution calculated with and without attenuation correction was also assessed. ResultsThe chest diameter was significantly longer in obese than in lean rats (5.6±0.3cm in obese and 4.5±0.2cm in lean rats, p<0.0001). Whereas the activity reduction by attenuation was significantly greater in obese than in lean rats (44.1±2.5% and 5.1±3.1%, p<0.0001), the regional variation of tissue attenuation among the ventricular walls was minimal in both lean (p=0.73) and obese rats (p=0.65). ConclusionAttenuation correction is indispensable for accurate comparison of cardiac tracer activity between animals with different body size, whereas it can be omitted for evaluation of regional tracer distribution.

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia

The changes in the availability of striatal dopamine transporter and dopamine D2 receptor after mild focal ischemia in rats were measured using a small animal positron emission tomography system. Mild focal ischemia was induced by 20-minute middle cerebral artery occlusion. [11C]PE2I binding to dopamine transporter was transiently increased on the ipsilateral side of the striatum at 2 days after middle cerebral artery occlusion. On day 7 and 14 after middle cerebral artery occlusion, [11C]PE2I binding levels were decreased. In contrast, [11C]raclopride binding to dopamine D2 receptor in the ipsilateral striatum had not changed at 2 days after middle cerebral artery occlusion. [11C]Raclopride binding was significantly decreased on the ischemic side of the striatum at 7 and 14 days after middle cerebral artery occlusion. Moreover, on day 1 and 2 after middle cerebral artery occlusion, significant circling behavior to the contralateral direction was induced by amphetamine challenge. This behavior disappeared at 7 days after middle cerebral artery occlusion. At 14 days, circling behavior to the ipsilateral direction (middle cerebral artery occlusion side) was significantly increased, and that to the contralateral direction also appeared again. The present study suggested that amphetamine-induced circling behavior indicated striatal dopaminergic alterations and that dopamine transporter and dopamine D2 receptor binding could be key markers for predicting motor dysfunction after mild focal ischemia.

Performance evaluation of a LYSO-based PET scanner for monitoring of dose delivery in hadrontherapy

The DoPET scanner is a compact positron emission tomography (PET) device. It has been developed for monitoring the range of charged particles during therapy with hadron beams. Previous works have focused on the development and upgrade of the device and on data analysis. In this paper, a full performance characterization of the DoPET system in terms of the energy resolution, spatial resolution, sensitivity, uniformity, and noise equivalent count rate is reported. All measurements refer to an adapted version of the National Electrical Manufacturers Association (NEMA) NU 4 - 2008 protocol, which was written originally for small animal PET systems. Since DoPET is a dual head planar system, it requires a modified characterisation procedure with respect to those described for ring geometries as in the NEMA NU 4 - 2008 protocol. The presented procedure may be of interest for any other PET system with a similar geometry as DoPET.

Assessing brain immune activation in psychiatric disorders: clinical and preclinical PET imaging studies of the 18-kDa translocator protein.

Accumulating evidence from different lines of research suggests an involvement of the immune system in the pathophysiology of several psychiatric disorders. During recent years, a series of positron emission tomography (PET) studies have been published using radioligands for the translocator protein (TSPO) to study microglia activation in schizophrenia, bipolar I disorder, major depression, autism spectrum disorder, and drug abuse. The results have been somewhat conflicting, which could be due to differences both in patient sample characteristics and in PET methods. In particular, further work is needed to address both methodological and biological sources of variability in TSPO levels, a process in which the use of animal models and small animal PET systems can be a valuable tool. Given this development, PET studies of immune activation have the potential to further increase our understanding of disease mechanisms in psychiatric disorders, which is a requisite in the search for new treatment approaches. Furthermore, molecular imaging could become an important clinical tool for identifying specific subgroups of patients or disease stages that would benefit from treatment targeting the immune system.

Development of a Body Shield for Small Animal PET System to Reduce Random and Scatter Coincidences

For small animal positron emission tomography (PET) research using high radioactivity, such as dynamic studies, the resulting high random coincidence rate of the system degrades image quality. The random coincidence rate is increased not only by the gamma photons from inside the axial-field-of-view (axial-FOV) of the PET system but also by those from outside the axial-FOV. For brain imaging in small animal studies, significant interference is observed from gamma photons emitted from the body. Single gamma photons from the body enter the axial-FOV and increase the random and scatter coincidences. Shielding against the gamma photons from outside the axial-FOV would improve the image quality. For this purpose, we developed a body shield for a small animal PET system, the microPET Primate 4-ring system, and evaluated its performance. The body shield is made of 9-mm-thick lead and it surrounds most of a rat’s body. We evaluated the effectiveness of the body shield using a head phantom and a body phantom with a radioactivity concentration ratio of 1:2 and a maximum total activity of approximately 250 MBq. The random coincidence rate was dramatically decreased to ~1/10, and the noise equivalent count rate (NECR) was increased ~6 times with an activity of 7 MBq in the head phantom. The true count rate was increased to ~35% due to the decrease in system deadtime. The average scatter fraction was decreased to 1/2.5 with the body shield. Count rate measurements of rat were also conducted with an injection activity of approximately 25 MBq of [C-11]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([C-11]DASB) and approximately 70 and 310 MBq of 2-deoxy-2-(F-18)fluoro-D-glucose ([F-18]FDG). Using the body shield, [F-18]FDG images of rats were improved by increasing the amount of radioactivity injected. The body shield designed for small animal PET systems is a promising tool for improving image quality and quantitation accuracy in small animal molecular imaging research.

Use of Positron Emission Tomography for Real-Time Imaging of Biodistribution of Green Tea Catechin

The aim of this study was to achieve real-time imaging of the in vivo behavior of a green tea polyphenol, catechin, by positron emission tomography (PET). Positron-labeled 4″ -[11C]methyl-epigallocatechin gallate ([11C]Me-EGCG) was orally administered to rats, and its biodistribution was imaged for 60 min by using a small animal PET system. As the result, images of [11C]Me-EGCG passing through the stomach into the small intestines were observed; and a portion of it was quantitatively detected in the liver. On the other hand, intravenous injection of [11C]Me-EGCG resulted in a temporal accumulation of the labeled catechin in the liver, after which almost all of it was transferred to the small intestines within 60 min. In the present study, we succeeded in obtaining real-time imaging of the absorption and biodistribution of [11C]Me-EGCG with a PET system.

Development of a SiPM-based PET imaging system for small animals

Advances in small animal positron emission tomography (PET) imaging have been accelerated by many new technologies such as the successful incorporation of silicon photomultiplier (SiPM). In this paper, we have developed a compact, lightweight PET imaging system that is based on SiPM detectors for small animals imaging, which could be integrated into a multi-modality imaging system. This PET imaging system consists of a stationary detector gantry, a motor-controlled animal bed module, electronics modules, and power supply modules. The PET detector, which was designed as a multi-slice circular ring geometry of 27 discrete block detectors, is composed of a cerium doped lutetium–yttrium oxyorthosilicate (LYSO) scintillation crystal and SiPM arrays. The system has a 60mm transaxial field of view (FOV) and a 26mm axial FOV. Performance tests (e.g. spatial resolution, energy resolution, and sensitivity) and phantom and animal imaging studies were performed to evaluate the imaging performance of the PET imaging system. The performance tests and animal imaging results demonstrate the feasibility of an animal PET system based on SiPM detectors and indicate that SiPM detectors can be promising photodetectors in animal PET instrumentation development.

EGS5 simulations for the development of non-contacting system to online measure the radiotracer concentration in blood

*Quantitative Positron Emission Tomography (PET) studies require the blood sampling which is very inconvenient and painful for the patients, handling of radioactive samples is risky to the workers and lengthy as well as less efficient to the imaging centers. Various approaches are proposed to reduce the exposure to the workers and number of blood samples to comfort the patients but no one fulfills all the requirements. We are designing a non-contacting system which can in-situ measure the radiotracer concentration in the blood and hence, provide Plasma Time-Activity Curve (PTAC). As a first step we consider a conventional system used to measure the dose in Nuclear Power Plant Systems (NPPS) with High Purity Germanium (HPGe) detector and a small animal PET system with Lutetium Aluminum Garnet with Avalanche Photo Diodes (LuAG-APD) pixelated detector blocks. Monte Carlo Electron Gamma Shower (EGS) 5 simulation tool is used to analyze the suitability of the systems and results are presented for a conventional parallel disc-detector system, a proposed perpendicular disc-detector system and a LuAG-APD animal PET tomograph. Although the conventional NPPS dose measurement system has the advantage of on-site measurement and best energy resolution but suffers from low detection efficiency and cannot be used in our case. However, the LuAG based PET tomograph with high detection efficiency, good spatial resolution, acceptable energy resolution and flexible arrangement to increase detection efficiency seems to be a more appropriate candidate.

Time over threshold based multi-channel LuAG-APD PET detector

To achieve efficient signal processing, several time-based positron emission tomography (PET) systems using a large number of granulated gamma-ray detectors have recently been proposed. In this work described here, a 144-channel Pr:LuAG avalanche photodiode (APD) PET detector that uses time over threshold (ToT) and pulse train methods was designed and fabricated. The detector is composed of 12×12 Pr:LuAG crystals, each of which produces a 2mm×2mm×10mm pixel individually coupled to a 12×12 APD array, which in turn is connected pixel-by-pixel with one channel of a time over threshold based application-specific integrated circuit (ToT-ASIC) that was designed and fabricated using a 0.25μm 3.3V Taiwan Semiconductor Company complementary metal oxide semiconductor (TSMC CMOS) process. The ToT outputs are connected through a field-programmable gate array (FPGA) to a data acquisition (DAQ) system. Three front-end ASIC boards—each incorporating a ToT-ASIC chip, threshold control digital-to-analog converters (DACs), and connectors, and dissipating power at about 230mW per board—are used to read from the 144-channel LuAG-APD detector. All three boards are connected through an FPGA board that is programmed to calibrate the individual thresholds of the ToT circuits to allow digital multiplexing to form an integrated PET module with a measured timing resolution of 4.2ns. Images transmitted by this PET system can be successfully acquired through collimation masks. As a further implementation of this technology, an animal PET system consisting of eight gamma pixel modules forming a ring is planned.

The Role of Cardiac PET in Translating Basic Science into the Clinical Arena

Non-invasive imaging has become fundamental in translating findings from basic science research into clinical applications. In this aspect, positron-emission tomography (PET) offers important advantages over other common imaging modalities like single-photon emission computed tomography, computed tomography, and magnetic resonance imaging (MRI), since PET provides superior detection sensitivity in the evaluation of different cardiovascular targets and pathways at the cellular and subcellular level, and because it is a well-established technique for absolute image quantification. The development and the introduction of dedicated small animal PET systems have greatly facilitated and contributed to advancements in the translation of novel radio-labeled compounds from experimental to clinical practice. The scope of the present article is to review the most relevant and successful PET applications in cardiovascular translational research.

Abstract 5302: Early prediction of response to therapy in malignant lymphoma using non-invasive [18F]FLT-PET imaging from animal to human model

Abstract Purpose: Preclinical and clinical studies have recently shown that the thymidine analogue [18F]fluorothymidine (FLT) accumulates in tumor tissue and enables non-invasive imaging of tumor proliferation, using positron emission tomography (PET). The aim of this study is to establish FLT-PET as an adequate and robust surrogate marker for very early response assessment to therapy in malignant Lymphoma. Methods: In animal models we assessed the thymidine metabolism in SCID mice bearing SUDHL-1 or Karpas 299 lymphoma prior to and early in the course of therapy with Hsp90 inhibitor NVP-AUY922 or mTOR inhibitor RAD001, using a small animal PET system. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of FDG-PET. PET findings were correlated with histopathology and in vitro data comprising cellular tracer uptake, cell cycle related protein expression, cell cycle distribution and viability assessment. In human models, FLT-PET was performed additionally to routine staging procedures in 66 patients with malignant lymphoma undergoing R-CHOP chemotherapy. FLT-uptake was correlated with response and survival. Results: SUDHL-1 cells proved to be sensitive to both inhibitors whereas Karpas299 showed relative resistance to NVP-AUY922. Tumor volume in treated animals bearing SUDHL-1 lymphomas showed modest increase within the first week (median increase = + 25%, range -30% to + 80%, n=8) as opposed to a 3.8-fold increase in control mice. After 14 days a clear reduction of tumor mass was observed (median = – 25%, range -40% to + 30%, n=4). Median TBR of FLT-PET decreased significantly to 40% compared to baseline as early as 5d after therapy (range 32-67%, n=8, p=0,008). In contrast, TBR in FDG-PET did not show any clear tendency (median TBR 79%, range 36%-161%, n=8, p=0.73). According to our in vitro results, less effect was seen during treatment with AUY299 resulting in an increase of median TBR in FLT-PET to 154% (p=0,008, n=11) on day 2. In contrast, mice receiving RAD001 showed a stronger inhibition of tumor development and early FLT-PET imaging indicated a decrease of TBR to 78% (n=9, p=0.008). In human data, the initial SUVmesn in complete responders was significantly lower than in patients with progressive disease or partial response (p=0.049). Conclusion: FLT-PET has a high specificity for the detection of malignant lymphomas, both in animal xenotransplants model and in human disease. Compared with FDG-PET, FLT-PET is able to predict response to specific inhibitors treatment very early in the therapeutic course. Our human data indicate that high initial FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell NHL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5302. doi:10.1158/1538-7445.AM2011-5302