Small Positron Emission Tomography Research Articles

Resolução espacial de um tomógrafo PET de pequenos animais usando o isótopo <sup>68</sup>Ga

Nuclear Medicine is a modality that has been growing a lot in Brazil and in the world, bringing new radiopharmaceuticals and technologies for the diagnosis and treatment of diseases, making them more effective and accurate. In the development of new radiopharmaceuticals for use in positron emission tomography (PET), the preclinical studies step largely uses PET scanners dedicated to small animals. To achieve this, quality control tests must be carried out to ensure the efficiency of the equipment. Thus, this work aimed to evaluate the spatial resolution of the small animals PET scanner of the CDTN using the isotope 68Ga. In this sense, a microPET hot rod phantom and a commercial 68Ge/68Ga generator were used to obtain PET images. The analysis of the 68Ga-PET images of the simulator was carried out qualitatively and quantitatively and revealed that the spatial resolution of the system using the 68Ga is 3.5 mm.

A multi-instance tumor subtype classification method for small PET datasets using RA-DL attention module guided deep feature extraction with radiomics features

Background:Positron emission tomography (PET) is extensively employed for diagnosing and staging various tumors, including liver cancer, lung cancer, and lymphoma. Accurate subtype classification of tumors plays a crucial role in formulating effective treatment plans for patients. Notably, lymphoma comprises subtypes like diffuse large B-cell lymphoma and Hodgkin’s lymphoma, while lung cancer encompasses adenocarcinoma, small cell carcinoma, and squamous cell carcinoma. Similarly, liver cancer consists of subtypes such as cholangiocarcinoma and hepatocellular carcinoma. Consequently, the subtype classification of tumors based on PET images holds immense clinical significance. However, in clinical practice, the number of cases available for each subtype is often limited and imbalanced. Therefore, the primary challenge lies in achieving precise subtype classification using a small dataset. Method:This paper presents a novel approach for tumor subtype classification in small datasets using RA-DL (Radiomics-DeepLearning) attention. To address the limited sample size, Support Vector Machines (SVM) is employed as the classifier for tumor subtypes instead of deep learning methods. Emphasizing the importance of texture information in tumor subtype recognition, radiomics features are extracted from the tumor regions during the feature extraction stage. These features are compressed using an autoencoder to reduce redundancy. In addition to radiomics features, deep features are also extracted from the tumors to leverage the feature extraction capabilities of deep learning. In contrast to existing methods, our proposed approach utilizes the RA-DL-Attention mechanism to guide the deep network in extracting complementary deep features that enhance the expressive capacity of the final features while minimizing redundancy. To address the challenges of limited and imbalanced data, our method avoids using classification labels during deep feature extraction and instead incorporates 2D Region of Interest (ROI) segmentation and image reconstruction as auxiliary tasks. Subsequently, all lesion features of a single patient are aggregated into a feature vector using a multi-instance aggregation layer. Result:Validation experiments were conducted on three PET datasets, specifically the liver cancer dataset, lung cancer dataset, and lymphoma dataset. In the context of lung cancer, our proposed method achieved impressive performance with Area Under Curve (AUC) values of 0.82, 0.84, and 0.83 for the three-classification task. For the binary classification task of lymphoma, our method demonstrated notable results with AUC values of 0.95 and 0.75. Moreover, in the binary classification task of liver tumor, our method exhibited promising performance with AUC values of 0.84 and 0.86. Conclusion:The experimental results clearly indicate that our proposed method outperforms alternative approaches significantly. Through the extraction of complementary radiomics features and deep features, our method achieves a substantial improvement in tumor subtype classification performance using small PET datasets.

Development of New CD38 Targeted Peptides for Cancer Imaging

PurposeMultiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges.ProceduresUsing phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems.ResultsThe CD38-targeted bioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 – 6.6 MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291 nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4 h. Clearance from non-target organs occurred within 60 min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4 h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1 h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4 h).ConclusionsThe novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

Broad-scope Syntheses of [11 C/18 F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts.

Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t1/2 =20.4 min) or fluorine-18 (t1/2 =109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no-carrier-added [11 C]CuCF3 or [18 F]CuCF3 . The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron-donating or electron-withdrawing groups at meta- or para- position are good to excellent (67-96 %). Ortho-substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15-34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [11 C]p-trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3-trifluoromethyl-4-aminopyridine, as examples of small drug-like molecules and candidate PET radioligands, were successfully labeled in high yields (69-81 %).

Investigation of Novel Preclinical Total Body PET Designed With J-PET Technology: A Simulation Study

The growing interest in human-grade total body positron emission tomography (PET) systems has also application in small animal research. Due to the existing limitations in human-based studies involving drug development and novel treatment monitoring, animal-based research became a necessary step for testing and protocol preparation. In this simulation-based study two unconventional, cost-effective small animal total body PET scanners (for mouse and rat studies) have been investigated in order to inspect their feasibility for preclinical research. They were designed with the novel technology explored by the Jagiellonian-PET (J-PET) Collaboration. Two main PET characteristics: sensitivity and spatial resolution were mainly inspected to evaluate their performance. Moreover, the impact of the scintillator dimension and time-of-flight on the latter parameter was examined in order to design the most efficient tomographs. The presented results show that for mouse TB J-PET the achievable system sensitivity is equal to 2.35% and volumetric spatial resolution to 9.46 ± 0.54 mm3, while for rat TB J-PET they are equal to 2.6% and 14.11 ± 0.80 mm3, respectively. Furthermore, it was shown that the designed tomographs are almost parallax-free systems, hence, they resolve the problem of the acceptance criterion tradeoff between enhancing spatial resolution and reducing sensitivity.

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies.

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (11C; t½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years.

The Application of in silico Methods for Prediction of Blood-Brain Barrier Permeability of Small Molecule PET Tracers.

Designing positron emission tomography (PET) tracers for targets in the central nervous system (CNS) is challenging. Besides showing high affinity and high selectivity for their intended target, these tracers have to be able to cross the blood-brain barrier (BBB). Since only a small fraction of small molecules is estimated to be able to cross the BBB, tools that can predict permeability at an early stage during the development are of great importance. One such tool is in silico models for predicting BBB-permeability. Thus far, such models have been built based on CNS drugs, with one exception. Herein, we sought to discuss and analyze if in silico predictions that have been built based on CNS drugs can be applied for CNS PET tracers as well, or if dedicated models are needed for the latter. Depending on what is taken into account in the prediction, i.e., passive diffusion or also active influx/efflux, there may be a need for a model build on CNS PET tracers. Following a brief introduction, an overview of a few selected in silico BBB-permeability predictions is provided along with a short historical background to the topic. In addition, a combination of previously reported CNS PET tracer datasets were assessed in a couple of selected models and guidelines for predicting BBB-permeability. The selected models were either predicting only passive diffusion or also the influence of ADME (absorption, distribution, metabolism and excretion) parameters. To conclude, we discuss the potential need of a prediction model dedicated for CNS PET tracers and present the key issues in respect to setting up a such a model.

Comparison of the Amyloid Load in the Brains of Two Transgenic Alzheimer's Disease Mouse Models Quantified by Florbetaben Positron Emission Tomography.

Alzheimer’s disease (AD) is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain, which can be mimicked by transgenic mouse models. Here, we report on the characterization of amyloid load in the brains of two transgenic amyloidosis models using positron emission tomography (PET) with florbetaben (FBB), an 18F-labeled amyloid PET tracer routinely used in AD patients. Young, middle-aged, and old homozygous APP/PS1 mice (ARTE10), old hemizygous APPswe/PS1ΔE9, and old wild-type control mice were subjected to FBB PET using a small animal PET/computed tomography scanner. After PET, brains were excised, and ex vivo autoradiography was performed. Plaque pathology was verified on brain sections with histological methods. Amyloid plaque load increased progressively with age in the cortex and hippocampus of ARTE10 mice, which could be detected with both in vivo FBB PET and ex vivo autoradiography. FBB retention showed significant differences to wild-type controls already at 9 months of age by both in vivo and ex vivo analyses. An excellent correlation between data derived from PET and autoradiography could be obtained (rPearson = 0.947, p < 0.0001). Although amyloid load detected by FBB in the brains of old APPswe/PS1ΔE9 mice was as low as values obtained with young ARTE10 mice, statistically significant discrimination to wild-type animals was reached (p < 0.01). In comparison to amyloid burden quantified by histological analysis, FBB retention correlated best with total plaque load and number of congophilic plaques in the brains of both mouse models. In conclusion, the homozygous ARTE10 mouse model showed superior properties over APPswe/PS1ΔE9 mice for FBB small animal amyloid PET imaging. The absolute amount of congophilic dense-cored plaques seems to be the decisive factor for feasibility of amyloidosis models for amyloid PET analysis.

Compound‐Specific Imaging of Methanol Fuel Cell for Performance and Degradation Studies Using a Mini Positron Emission Tomograph

AbstractDirect methanol fuel cell is a promising electrical energy source. Performance improvements, such as higher energy density and improved electrocatalyst are hot topics in fuel cell research. The goal of this study is the introduction of the Positron Emission Tomography (PET) as molecular imaging technique in the visualization of the methanol fuel cell process. The compound specific imaging method, using a small PET camera and radiolabeled 11C methanol, can visualize the electrocatalytic processes, the coverage degree and the distribution of the methanol and its derivatives on the total electrocatalyst surface. The undesirable methanol crossover effect was also detected by imaging the additional layers of the cell. The fuel cell layers were studied in different conditions, such as well‐functioning and temporarily or permanently degraded, during short‐ and long‐term operations. The experimental results confirmed the PET imaging method is applicable in the methanol fuel cell development.

Field-programable-gate-array-based distributed coincidence processor for high count-rate online positron emission tomography coincidence data acquisition

For positron emission tomography (PET) online data acquisition, a centralized coincidence processor (CCP) with single-thread data processing has been used to select coincidence events for many PET scanners. A CCP has the advantages of highly integrated circuit, compact connection between detector front-end and system electronics and centralized control of data process and decision making. However, it also has the drawbacks of data process delay, difficulty in handling very high count-rates of single and coincidence events and complicated algorithms to implement. These problems are exacerbated when implementing a CCP on a field-programable-gate-array (FPGA) due to increased routing congestion and reduced data throughput. Industry companies have applied non-centralized or distributed data processing to solve these problems, but those solutions remain either proprietary or lack full disclosure of technical details that make the techniques unclear and difficult to adapt for most research communities. In this study, we investigated the use of a set of distributed coincidence processors (DCP) that can address the CCP problems and be implemented relatively easily. Each coincidence processor exclusively connects one detector pair and selects coincidence events from this detector pair only, which breaks a centralized coincidence process to a collection of independent and parallel processes. DCP can significantly minimize the data process delay, maximize count-rates of coincidence events and simplify implementation by implementing a single coincidence processor with one detector pair and replicating it to the rest. A prototype DCP with 42 coincidence processors was implemented on an off-the-shelf FPGA development board for a small PET with 12 detectors configured with 42 detector pairs. DCP performances were tested with both pulsed signals and gamma ray interactions. There was no coincidence data loss up to the detector’s maximum singles count-rate (250 k s−1). Approximately 1.2 k registers were utilized for each coincidence processor and the FPGA resource utilization was proportional to the number of coincidence processors. Coincidence timing spectra showed the results from accurately acquired coincidence events. In conclusion: complementary to CCP, DCP can provide high count-rate capability, with a simplified algorithm for implementation and potentially a practical solution for online acquisition of a PET with a larger number of detector pairs or for ultrahigh-throughput imaging.

One-step radiosynthesis and initial evaluation of a small molecule PET tracer for PD-L1 imaging

Programmed cell death protein-ligand 1 (PD-L1) is a crucial biomarker in immunotherapy and its expression level plays a key role in the guidance of anti-PD-L1 therapy. It had been reported that PD-L1 was quantified by noninvasive imaging with more developed radiotracers. In our study, a novel [18F]fluoride labeled small molecule inhibitor, [18F]LN was designed for positron emission tomography (PET) imaging in both PD-L1 transfected (A375-hPD-L1) and non-transfected (A375) melanoma-bearing mice. LN showed the specificity (IC50 = 50.39 ± 2.65 nM) to PD-L1 confirmed by competitive combination and cell flow cytometry (FACS) analysis. The radiotracer [18F]LN was obtained via 18F-19F isotope exchange from precursor LN. After radiosynthesis, [18F]LN was achieved with a high radiochemical purity (RCP) above 95% and got a favorable molar activity of 36.34 ± 5.73 GBq/μmol. [18F]LN displayed the moderate affinity (Kd = 65.27 ± 3.47 nM) to PD-L1 by specific binding assay. And it showed 1.3-fold higher uptake in A375-hPD-L1 cells than that in A375 cells. PET imaging revealed that [18F]LN could enter into PD-L1 expressing tumor site and visualize the outline of tumor. And tumor uptake (1.96 ± 0.27 %ID/g) reached the maximum at 15 min in the positive group, showed 2.2-fold higher than the negative (0.89 ± 0.31 %ID/g) or the blocked (1.07 ± 0.26 %ID/g) groups. Meanwhile, biodistribution could slightly distinguish the positive from the negative. The results indicated [18F]LN would become an efficient tool for evaluating PD-L1 expression with further optimization.

Research progress of 18F labeled small molecule positron emission tomography (PET) imaging agents.

With the development of positron emission tomography (PET) technology, a variety of PET imaging agents labeled with radionuclide 18F have been developed and widely used in the diagnosis and treatment of various clinical diseases in recent years. For example, they have showed a great value of study in the field of tumor detection, tumor treatment and evaluation of tumor therapy in a non-invasive, qualitative and quantitative way. In this review, we highlight the recent development in chemical synthesis, structure and characterization, imaging characterization, and potential applications of these 18F labeled small molecule PET imaging agents for the past five years. The development and application of 18F labeled small molecules will expand our knowledge of the function and distribution of diseases-related molecular targets and shed light on the diagnosis and treatment of various diseases including tumors.

Validation of a spatially variant resolution model for small animal brain PET studies

In small animal positron emission tomography (PET) studies, given the spatial resolution of preclinical PET scanners, quantification in small regions can be challenging. Moreover, in scans where animals are placed away from the center of the field of view (CFOV), e.g. in simultaneous scans of multiple animals, quantification accuracy can be compromised due to the loss of spatial resolution towards the edge of the FOV. Here, we implemented a spatially variant resolution model to improve quantification in small regions and to allow simultaneous scanning of multiple animals without compromising quantification accuracy. The scanner’s point spread function (PSF) was characterized across the FOV and modelled using a spatially variant and asymmetric Gaussian function. The spatially variant PSF (SVPSF) was then used for resolution modelling in the iterative reconstruction. To assess the image quality, a line source phantom in a cold and warm background, as well as mouse brain [18F]FDG scans, were performed. The SVPSF and the vendor’s maximum a posteriori (MAP3D) reconstructions produced uniform spatial resolution across the scanner FOV, but MAP3D resulted in lower spatial resolution. The line sources recovery coefficient using SVPSF was similar at the CFOV and at the edge of the FOV. In contrast, the other tested reconstructions produced lower recovery coefficient at the edge of the FOV. In mouse brain reconstructions, less spill-over from hot regions to cold regions, as well as more symmetric regional brain uptake was observed using SVPSF. The contrast in brain images was the highest using SVPSF, in mice scanned at the CFOV and off-center. Incorporation of a spatially variant resolution model for small animal brain PET improves quantification accuracy in small regions and produces consistent image spatial resolution across the FOV. Therefore, simultaneous scanning of multiple animals can benefit by using spatially variant resolution modelling.

Design study of a brain-dedicated time-of-flight PET system with a hemispherical detector arrangement

Time-of-flight (TOF) is now a standard technology for positron emission tomography (PET), but its effective use for small diameter PET systems has not been studied well. In this paper, we simulated a brain-dedicated TOF-PET system with a hemispherical detector arrangement. We modeled a Hamamatsu TOF-PET module (C13500-4075LC-12) with 280 ps coincidence resolving time (CRT), in which a 12 × 12 array of multi pixel photon counters (MPPCs) is connected to a lutetium fine silicate (LFS) crystal array of 4.1 × 4.1 mm2 cross section each, based on one-to-one coupling. On the other hand, spatial resolution degradation due to the parallax error should be carefully addressed for the small diameter PET systems. The ideal PET detector would have both depth-of-interaction (DOI) and TOF capabilities, but typical DOI detectors that are based on light sharing tend to degrade TOF performance. Therefore, in this work, we investigated non-DOI detectors with an appropriate crystal length, which was a compromise between suppressed parallax error and decreased sensitivity. Using GEANT4, we compared two TOF detectors, a 20 mm long non-DOI and a 10 mm long non-DOI, with a non-TOF, 4-layer DOI detector with a total length of 20 mm (i.e. 5 × 4 mm). We simulated a contrast phantom and evaluated the relationship between the contrast recovery coefficient (CRC) and the noise level (the coefficient of variation, COV) for reconstructed images. The 10 mm long non-DOI, which reduces the parallax error at the cost of sensitivity loss, showed better imaging quality than the 20 mm long non-DOI. For example, the CRC value of a 10 mm hot sphere at COV = 20% was 72% for the 10 mm long non-DOI, which was 1.2 times higher than that of the 20 mm long non-DOI. The converged CRC values for the 10 mm long non-DOI were almost equivalent to those of the non-TOF 4-layer DOI, and the 10 mm long non-DOI converged faster than the non-TOF 4-layer DOI did. Based on the simulation results, we evaluated a one-pair prototype system of the TOF-PET detectors with 10 mm crystal length, which yielded the CRT of 250 ± 8 ps. In summary, we demonstrated support for feasibility of the brain-dedicated TOF-PET system with the hemispherical detector arrangement.

SiPM-based dual-ended-readout DOI-TOF PET module based on mean-time method

Positron emission tomography (PET) with high resolution and high sensitivity is desirable for detecting cancers and neurological diseases. In this work, a depth-of-interaction (DOI)-time-of-flight (TOF) PET has been attempted to achieve both high spatial and high timing resolution. Dual-ended readout is a simple technique that can provide excellent timing and DOI resolutions and consistent signal arrival times, regardless of the DOI position along the scintillation crystal, as a mean-time method is used. A dual-ended readout DOI-TOF PET module consisting of a 6 × 6 array of 2 × 2 × 20 mm3 saw-cut cerium-doped lutetium-yttrium oxyorthosilicate (LYSO) crystals is constructed. Both ends of the LYSO crystal array are optically coupled to a multi-pixel photon counter (MPPC) with 4 × 4 channels. The sixteen MPPC outputs are reduced to four position signals using a charge division circuit (CDC) board, and the timing signal is extracted from the common cathode of the MPPC. The four position signals from the MPPC are digitized by a DRS4-based high-speed waveform digitizer with a sampling rate of 5 GSa/s. A 22Na source is placed in front of a reference detector and at the side of the dual-ended readout DOI-TOF PET module in five steps of 2 mm, 6 mm, 10 mm, 14 mm, and 18 mm to measure the DOI, coincidence timing resolutions (CTRs), and mean-times. The full-width-half-maximums (FWHMs) of DOI resolutions and CTRs varied from 3.0 mm to 3.8 mm, with an average of 3.5 mm, and from 333 ps to 367 ps, with an average of 349 ps, respectively. The average of the slopes of the mean-time versus DOI position, for the 36 crystals, was −0.60 ± 1.68 ps/nm, which was consistent with the null value. The dual-ended readout DOI-TOF PET module based on the mean-time method produced both good DOI and CTRs, and consistent signal arrival times. The found solution would be the most advantageous in the small aperture PET systems, such as those for brain and breast imaging.

Evaluation of Position Resolution for a Prototype Whole-Body PET Detector Based on Suppressing Backgrounds by Compton Scattering

Existing PET (Positron Emission Tomography) systems make clear images in demonstration (measuring small PET reagent in pure water), however images in real diagnosis become unclear. The authors suspected that this problem was caused by Compton scattering in a detector. When PET systems observe plural photomultiplier tube outputs, an original emission point is regarded as centroid of the outputs. However, even if plural emission in Compton scattering occur, these systems calculate original point in the same way as single emission. Therefore, the authors considered that rejecting Compton scattering events makes PET systems much better, and made prototype counter. Main components of the prototype counter are plate-like high-growth-rate (HGR) La-GPS scintillators and wavelength shifting fibers (WLSF). HGR crystals grow 10 times as fast as a mono-crystal (a normal mono-crystal grows at 2 – 3 mm an hour). Thus, it includes microbubble and its transparency get worth. Consequently, HGR crystals usually are not used in radiation measuring instruments. However, this time they are used on the purpose. Because of their low transparency, scintillation lights come out right above and right under of emission position. Therefore, Compton scattering events is rejected easily. The prototype detector has an effective area of 300 by 300 square mm. The detector consists of 24 layers. One layer consists of HGR La-GPS scintillator of 1 mm thickness. Top and bottom surface of scintillator were covered by dual sheets of WLSF with a diameter of 0.2 mm. Sheets of WLSF on top and bottom of the scintillator make a right angle with each other, and measure X- and Y-components. Z-component is measured by difference of WLSF outputs between top and bottom. If plural layers output signals, this counter regards the event as Compton scattering event, and reject the event. Even if only a layer output signals, the event is rejected when number output signals from WLSF is more than 1.5 times of single emission. Material cost of this system is, 0.2M$ for HGR La-GPS, 0.03M$ for WLSF, 0.03M$ for 600 units of 6 by 6 mm SiPM's, 0.12M$ for 12000 units of 1 by 1 mm SiPM's, and 0.09M$ for 1800 channel of signal readout circuits. Considering total cost, price of this PET will be set 1M$ or less. This idea was confirmed with numerical simulation and experimentation. In experimentation, position resolution in photoelectric absorption was 0.2 mm, and minimum distance that this detector could recognize plural emission in Compton scattering was 1 mm. In parallel, three kinds of model were made: a prototype detector, all the signals readout method, and resistance delay method. Simulation setting was 2 MBq/L in normal tissue and 10 MBq/L in cancer. As a result of simulation, a prototype detector identified 3 mm cancer, however the others made unclear image and was not able to identified cancer. That is to say, the prototype detector is able to reject Compton scattering events and inexpensive. Therefore, whole-body PET system with this detector must diagnose cancer with a diameter of 3 mm or more and be priced 1M$ or less

Activated Microglia in the Brain: Mitochondrial and Cell Membrane-Associated Targets for Positron Emission Tomography

The emission tomographic imaging of activated microglia in the brain moves into the focus of neuroscientific research with increasing recognition of contributions of early inflammatory processes to neurodegenerative, traumatic, cancerous and infectious diseases of the brain. Whereas the mitochondrial isoform of the 18 kDa translocator protein (TSPO1) has been the main cellular target for positron emission tomography (PET) of this type of cells for decades, alternative marker proteins in the plasma membrane of microglia challenge efforts in ligand development, recently. The present report includes PET approaches using the chemokine receptor CX3CR1 and the FR2 folate receptor in parallel to small molecule PET tracers available for in vivo visualization of the “classical” target TSPO1. It compares first and second generation of TSPO1 ligands as well as new compounds like the tetrahydrocarbazole [18F]GE-180 and the quinazoline [11C]ER176 presumed to reduce polymorphism-related inter-subject variations, with allosteric ligands for the chemokine receptor CX3CR1 and with radio labelled folate conjugates targeting the folate “cargo” receptor FR1 and the FR2 receptor characteristic for anti-inflammatory M2 microglia.

Fast and Accurate Rat Head Motion Tracking With Point Sources for Awake Brain PET.

To avoid the confounding effects of anesthesia and immobilization stress in rat brain positron emission tomography (PET), motion tracking-based unrestrained awake rat brain imaging is being developed. In this paper, we propose a fast and accurate rat headmotion tracking method based on small PET point sources. PET point sources (3-4) attached to the rat's head are tracked in image space using 15-32-ms time frames. Our point source tracking (PST) method was validated using a manually moved microDerenzo phantom that was simultaneously tracked with an optical tracker (OT) for comparison. The PST method was further validated in three awake [18F]FDG rat brain scans. Compared with the OT, the PST-based correction at the same frame rate (31.2 Hz) reduced the reconstructed FWHM by 0.39-0.66 mm for the different tested rod sizes of the microDerenzo phantom. The FWHM could be further reduced by another 0.07-0.13 mm when increasing the PST frame rate (66.7 Hz). Regional brain [18F]FDG uptake in the motion corrected scan was strongly correlated ( ) with that of the anesthetized reference scan for all three cases ( ). The proposed PST method allowed excellent and reproducible motion correction in awake in vivo experiments. In addition, there is no need of specialized tracking equipment or additional calibrations to be performed, the point sources are practically imperceptible to the rat, and PST is ideally suitable for small bore scanners, where optical tracking might be challenging.

Small Molecule-Assisted PET: Approaches to Imaging of Conformational Diseases of the Brain

PET (positron emission tomography) in vivo imaging of cerebral conformational diseases is essentially based on non-peptide small molecule ligands used to detect early alterations in peptide secondary structures and subsequent accumulation of aberrant oligomers and protein deposits involved in progressive neurodegeneration, cognitive and movement disorders. In this article, an overview is given about tracers currently available and lead structures of potential PET probes for detection of β-amyloid (Aβ), tau protein, α-synuclein, constitutive (PrPc) and infectious isoforms (PrPsc) of prions (proteinaceous infectious particles) as imaging targets. Whereas the styrylpyridine derivative florbetapir, approved for clinical applications, the stilbene derivative florbetaben and the benzoxazole derivative BF227 show high affinity binding to Aβ, preclinical investigations promise improved pharmacokinetics for benzoimidazothiazoles, aryloxazoles and benzofuran derivatives. Tau protein imaging based clinically, presently, on the pyridine-pyridoindole T807 has got new incentives following identification of a series of pyrrolopyridine quinolines and pharmacokinetic improvements of fluoropropoxy quinolines including for instance THK-5351. The pyridine isoquinoline MK6240 is involved now in clinical trials. Most forward-looking efforts apply to small molecule ligands of α-synuclein, which are expected to permit a breakthrough in differential diagnostics of Parkinson-related dementia and Lewy body diseases. However, at the moment the proposed lead structures are in affinity and blood brain barrier delivery properties below the possibilities of Aβ and tau protein ligands. This is the case also for potential tracers of prion proteins.

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.