Radiolabeled peptides are valuable tools for diagnosis or therapies; they are often radiofluorinated using an indirect approach based on an F-18 prosthetic group. Herein, we are reporting our results on the F-18 radiolabeling of three peptides using two different methods based on click reactions. The first one used the well-known CuAAC reaction, and the second one is based on our recently reported hetero-Diels–Alder (HDA) using a dithioesters (thia-Diels–Alder) reaction. Both methods have been automated, and the 18F-peptides were obtained in similar yields and synthesis time (37–39% decay corrected yields by both methods in 120–140 min). However, to obtain similar yields, the CuAAC needs a large amount of copper along with many additives, while the HDA is a catalyst and metal-free reaction necessitating only an appropriate ratio of water/ethanol. The HDA can therefore be considered as a minimalist method offering easy access to fluorine-18 labeled peptides and making it a valuable additional tool for the indirect and site-specific labeling of peptides or biomolecules.

Positrons are widely used in molecular imaging through the Positron Emission Tomography (PET) imaging technique. However PET only reconstruct the distribution of the positron emitting radioisotopes, and because the β+ isotopes are linked to a vector molecule, the distribution of β+ isotopes is correlated to the distribution of a given biological function. Positron-electron annihilation can transit through a meta-stable called positronium, which can exist in two spin states: the single state -parapositronium -and the triplet state -orthopositronium. The orthopositronium lifetime (τoPs), formation probabilities and decay modes are sensitive to the physical and chemical state of the neighboring medium and could therefore provide information on the tissues themselves during a PET acquisition. However, traditional PET only relies on the detection of the two annihilation photons, therefore the lifetime and annihilation higher multiplicity annihilations are not accessible to such PET paradigm. This review will present some of the use cases of positronium as a specific signature for event selection in astrophysics and particle physics, and as a probe for the microscopic state of materials and tissues. These usages of positronium highlight the interest for positronium for diagnostic in medical science, the projects for using positronium in upcoming PET tomographs are then presented.

The concept of imaging several subjects simultaneously is an active preclinical research topic. In this article, we assessed the imaging capabilities of two positron emission tomograph (PET)/computed tomograph (CT) systems based on similar detector technology. The IRIS system is a mice/rat imaging system arranged in two rings of eight detectors each, the more recent IRIS XL 260, dedicated to nonhuman primate (NHP) imaging has a single ring of 16 detectors. Both systems were equipped with standard animal cells (Minerve) and 3-mice adapters. Our objective is to study which of these systems could be more appropriate to perform quantitative high-throughput imaging on mice. Phantoms and [18F]FDG tumor-bearing mice acquisitions have been conducted in single- and high-throughput modes using both the IRIS (up to 3 mice) and the IRIS XL-260 PET/CT (up to 6 mice) systems. Image quality phantom results obtained in high-throughput mode show some slight degradation of the recovery coefficient for rods of 1, 2, and 3 mm in diameter compared to the single-mode results, as one would normally expect. Similarly, we observed a decrease in image uniformity between the single- and the high-throughput modes for both the IRIS PET and the IRIS XL-260 PET systems. We performed [18F]FDG tumor-bearing mice PET acquisitions with both systems. In order to estimate the quantification differences in all the studied configurations, we calculate the ratios between the %ID/g values extracted from the PET images and the ex-vivo values. In single-mode acquisitions, ratios of 0.94 ± 0.09 and 0.83 ± 0.08 were obtained for the IRIS and the IRIS XL-260 PET systems, respectively. In high-throughput mode, ratios of 0.78 ± 0.12 and 0.73 ± 0.13 were obtained for the IRIS and the IRIS XL-260 PET systems, respectively. The difference in %ID/g between static acquisitions and ex-vivo value is not statistically significant ( $p$ -value > 0.1) for both PET systems in single mode, as well as for the IRIS system in the high-throughput mode. We noted a slightly higher statistical difference between static acquisitions and ex-vivo values for the IRIS XL-260 system with a $p$ -value of 0.015. Phantoms and in-vivo studies have made it possible to highlight the capability of the two systems to perform high-throughput acquisitions. Our results suggest that the IRIS system configuration may be the most suitable when aiming for quantitative high-throughput mice imaging. The large transverse field of view of the IRIS XL-260 makes it possible to image a greater number of mice simultaneously, which may be useful in specific cases, such as studies using an expensive radiotracer and/or with a short half-life. However, the IRIS PET/CT offers a full axial coverage of the animals and a higher sensitivity.

In the context of preclinical tomographic imaging, the readout electronics of radiation detectors measures the charge and time of signals. An interesting electronic architecture is the cascade of charge-to-time converters (QTC) with time-to-digital converters (TDC). We propose a non-gated QTC circuit with the fewest standard discrete components known in the literature. The proposed converter only consists in one amplifier and one MOSFET transistor wired in negative feedback while providing a Time-over-Threshold (ToT) response to the input charge. For negative or positive detector output current, the MOSFET is a n-channel or a p-channel respectively. The transistor in saturation regime operates simultaneously a charge integration with its intrinsic capacitance and a constant current discharge. An additional capacitor in parallel of the MOSFET can extend the functional charge range. A n-MOSFET QTC prototype board was designed and tested with both a digital detector emulator and a detector irradiated with a 99m Tc source. Preliminary results of ToT in function of charges show a relative error less than 3.5 % with linear fit, on the range from 0.9 pC to 21.9 pC. Future work will focus on using a Field-Programmable-Gate-Array (FPGA) which will include the TDC function but also the discriminator function using a single-ended voltage-referenced input receiver.

We propose positron transmission imaging as a novel concept of imaging modality that will use a uniform β + source to illuminate a tissue sample with positrons in order to image the electronic density of histological tissues slices with a ~50μm resolution. This imaging modality will be implemented as part of a high resolution 2D τ OPs imager to serve as reference anatomical image to a τ OPs image. We will describe the imager layout, present the concept of the e + transmission imaging modality, and the results of preliminary simulations evaluating the expected count rate for the various layers of the imager, the expected sensitivity and spatial resolution of the reconstructed image.

A thia-Diels-Alder reaction between a phosphonodithioester and a highly reactive exocyclic diene for the chemoselective labeling of peptides under catalyst-free mild conditions is described. An efficient method to introduce the dithioester function into a model tripeptide was first developed and then applied to two bioactive peptides, PSMA and apelin-13. The tripeptide-dithioester was used to optimize the cycloaddition with dienes bearing fluorine-18 or a fluorophore. Then, the cycloaddition of the PSMA-dithioester with the F-18-diene led to a new PSMA-radiotracer, which was used for in vivo Positron Emission Tomography (PET) imaging. In the same way, a fluorescent apelin-13 probe was obtained from the apelin-dithioester and a squaraine-linked diene before beingused for in cellulo optical imaging.

A major strength of iterative algorithms used in positron emission tomography (PET) lies in their abilities to introduce precise models of the physics at play, which includes the statistical nature of the detection processes, and a detailed description of the radiation-matter interactions. The process of data acquisition by the imaging system is described in a system response model, or system response matrix (SRM). In PET, elements of this matrix correspond to a probability of a coincident pair of gamma emitted from a certain element of the imaged volume (voxel) to be detected by the apparatus along a given pair of detection elements (e.g. a pair of scintillating crystals), or line of response (LoR). The number of voxels involved for each line of response and the statistical error on each matrix element are directly dependent on the number of coincident events simulated to generate the SRM. The main goal of this paper is to first evaluate the behavior of these two parameters and secondly to estimate their impact on the overall image quality in preclinical PET imaging. Our results show the direct impact of the statistical variance of the Monte-Carlo generated System Response Matrices used in iterative reconstruction algorithms on image quality.

The HDA reaction of dithioesters was developed as a new click-reaction compatible with the indirect 18F-labelling of peptides. It involves dithioester-peptides and a radiofluorinated diene as a novel prosthetic group. The method was applied to a PSMA-ligand for the in vivo detection of LNCap tumors in xenografted mice.

64CuCl2 is an economic radiotracer for oncologic PET investigations. In the present study, we characterized the uptake of 64CuCl2 in vivo by µPET/CT in an allograft 4T1-related mouse model (BALB/c) of advanced breast cancer. 18F-FDG was used as a comparator. Twenty-two animals were imaged 7–9 days following 4T1-cell implantation inside mammary glands. Dynamic 64CuCl2 µPET/CT acquisition or iterative static images up to 8 h p.i. were performed. Animal biodistribution and tumor uptake were first evaluated in vivo by µPET analysis and then assessed on tissue specimens. Concerning 18F-FDG µPET, a static acquisition was performed at 15 min and 60 min p.i. Tumor 64CuCl2 accumulation increased from 5 min to 4 h p.i., reaching a maximum value of 5.0 ± 0.20 %ID/g. Liver, brain, and muscle 64CuCl2 accumulation was stable over time. The tumor-to-muscle ratio remained stable from 1 to 8 h p.i., ranging from 3.0 to 3.7. Ex vivo data were consistent with in vivo estimations. The 18F-FDG tumor accumulation was 8.82 ± 1.03 %ID/g, and the tumor-to-muscle ratio was 4.54 ± 1.11. 64CuCl2 PET/CT provides good characterization of the 4T1-related breast cancer model and allows for exploration of non-glycolytic cellular pathways potentially of interest for theragnostic strategies.

The main objective of the present study was to compare the 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) and 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) PET imaging biomarkers for the longitudinal follow-up of small animal proton therapy studies in the context of hepatocellular carcinoma (HCC). SK-HEP-1 cells were injected into NMRI nude mice to mimic human HCC. The behavior of [18F]-FDG and [18F]-FLT tumor uptake was evaluated after proton therapy procedures. The proton single-fraction doses were 5, 10, and 20 Gy, with a dose rate of 10 Gy/min. The experimental protocol consisted of 8 groups of 10 mice, each group experiencing a particular dose/radiotracer condition. A reference PET exam was performed on each mouse the day before the irradiation procedure, followed by PET exams every 3 days up to 16 days after irradiation. [18F]-FDG uptake showed a linear dose-dependent increase in the first days after treatment (37%, p < 0.05), while [18F]-FLT uptake decreased in a dose-dependent manner (e.g., 21% for 5 Gy compared to 10 Gy, p = 1.1e-2). At the later time point, [18F]-FDG normalized activity showed an 85% decrease (p < 0.01) for both 10 and 20 Gy doses and no variation for 5 Gy. Conversely, a significant 61% (p = 0.002) increase was observed for [18F]-FLT normalized activity at 5 Gy and no variation for higher doses. We showed that the use of the [18F]-FDG and [18F]-FLT radiolabeled molecules can provide useful and complementary information for longitudinal follow-up of small animal proton therapy studies in the context of HCC. [18F]-FDG PET imaging enables a treatment monitoring several days/weeks postirradiation. On the other hand, [18F]-FLT could represent a good candidate to monitor the treatment few days postirradiation, in the context of hypo-fractioned and close irradiation planning. This opens new perspectives in terms of treatment efficacy verification depending on the irradiation scheme.

Autoradiography (AR) is a technique used to record the spatial distribution of a radiotracer into an ex-vivo tissue slice. Within the section, the radioactive molecules emit charged particles from specific binding sites. These particles pass through the tissue before being detected by a sensor. AR gives the distribution of a radioactive molecule with a spatial resolution of approximately one hundred microns. In this article, we investigated the feasibility of AR with a CMOS-APS sensor using radioactive isotope 18F. This sensor works in digital mode by collecting charges. It presents a linear response with isotope 18F for activity between 1 kBq and 1 MBq. The detection efficiency is 44,0 ± 0.5% for this range of activity with a spatial resolution of 144 ± 3 μm by using the absorber edge method. The Mimosa-28 sensor performs AR imaging with a rose leaf and a mouse brain section which has a thickness of 50 μm and an activity of 4 kBq in the slice.

Nous avons évalué pour la première fois la fixation de la O-(2-[18F]-fluoroéthyl)-L-tyrosine (18F-FET) dans l’insulinome à partir d’un modèle de xénogreffe murine et chez un patient présentant une hypoglycémie hyperinsulinémique endogène. Dans les deux cas, une comparaison avec les données issues de la TEP à la 18F-FDOPA a été effectuée. Les analyses in vivo ont été réalisées sur des souris nudes porteuses d’une xénogreffe d’insulinome développée après injection sous-cutanée de cellules bêta murines RIN-m5F. Dix animaux ont été étudiés par microTEP avec acquisition dynamique après l’injection de 18F-FET (8,8 ± 1,7 MBq) ou 18F-FDOPA (5,1 ± 0,9 MBq) après prémédication par carbidopa. La preuve de concept clinique a été effectuée chez un homme âgé de 30 ans avec NEM1. Les examens TEP/TDM 18F-FET et 18F-FDOPA (après prémédication par carbidopa) ont été réalisés ainsi qu’une TEMP/TDM à l’111In-DTPA-exendine-4 avant la chirurgie pancréatique. Sept et trois animaux ont été, respectivement, étudiés par 18F-FET et 18F-FDOPA microTEP. La xénogreffe a été détectée chez tous les animaux imagés. La tumeur est caractérisée par une augmentation précoce de la fixation de la 18F-FET, suivie d’un déclin modéré de l’intensité au cours du temps. Les profils dynamiques de la fixation tumorale de la 18F-FET et 18F-FDOPA sont comparables. Chez le patient examiné, les examens TEP/TDM à la 18F-FET et 18F-FDOPA ont montré une hyperfixation focale concordante, bien définie, mais d’intensité modérée dans la queue pancréatique. La TEMP/TDM à l’111In-DTPA-exendine-4 met en évidence deux foyers d’hyperfixation intense, dont un dans la queue pancréatique (concordant avec les explorations TEP/TDM) et le deuxième dans le corps pancréatique, correspondant à deux insulinomes de 7 et 11 mm à l’examen anatomopathologique après chirurgie. Le profil dynamique de fixation de la 18F-FET est similaire entre l’insulinome humain et le modèle de xénogreffe animal. Dans le modèle pré-clinique d’insulinome considéré dans notre étude ainsi que chez un patient, la fixation de la 18F-FET est comparable à celle de la 18F-FDOPA. Cependant, les deux radiotraceurs sont sous-optimaux et moins performants que le dérivé de GLP-1 radiomarqué chez un patient présentant une hypoglycémie hyperinsulinémique endogène.

La prémédication par carbidopa semble améliorer la sensibilité de la TEP à la 18F-FDOPA pour le diagnostic d’insulinome. Cependant, un risque induit de résultats faux négatifs a été évoqué. Par conséquent, nous avons évalué in vitro (cellules β) et in vivo (xénogreffe animale d’insulinome) l’effet de la carbidopa sur la fixation de la 18F-FDOPA. L’accumulation in vitro de 18F-FDOPA a été évaluée dans la lignée murine cellulaire β RIN-m5F avec deux types de milieu de culture (déplété et non déplété en acides aminés) en présence et en absence d’un inhibiteur du transporteur de la 18F-FDOPA. Les expériences in vivo par microTEP ont été réalisées à partir d’un modèle de xénogreffe développé sur six souris nudes après injection sous-cutanée de cellules RIN-m5F. Les expériences ont été conduites avec et sans prétraitement à la carbidopa et la fixation évaluée en phase précoce et tardive. L’incubation de cellules RIN-m5F avec 80 μM de carbidopa n’a pas d’effet significatif sur l’accumulation cellulaire de 18F-FDOPA. Le niveau de captation du traceur semble toutefois dépendant du milieu de culture. In vivo, les xénogreffes sont dans tous les cas clairement détectables par microTEP. De plus, chez les souris prétraitées par carbidopa, les xénogreffes ont montré une fixation significativement plus importante de la 18F-FDOPA que celles des souris non traitées. Indépendamment de la prémédication de la carbidopa, les xénogreffes ont été caractérisées par une augmentation précoce de l’absorption de 18F-FDOPA et ensuite par une réduction progressive dans le temps. La carbidopa n’influence pas de manière significative l’accumulation in vitro de 18F-FDOPA dans les cellules RIN-m5F et améliore la visualisation de l’insulinome in vivo. Nos résultats augmentent les connaissances actuelles sur le profil de capture de la 18F-FDOPA par les cellules RIN-m5F et dans un modèle de xénogreffe apparenté. À notre connaissance, ce travail représente la première preuve préclinique.

Nowadays, the use of gold standard Monte Carlo Simulation (MCS) based modeling of the acquisition process in a way to compute the System Matrix (SM) is one of the well-established methods that has been used in small animal SPECT image reconstruction. However, MCS requires extensive computation time to obtain a low noise SM. Such reconstruction methods are therefore largely penalized by the huge time consumption required for the SM generation since a large number of photons has to be generated: an improvement in simulation speed is thus mandatory. Simplified analytical approach has the potential to lead to efficient SM computation, in a reduced time while requiring neither particular computing skills nor heavy informatics resources (cluster). In this work, we proposed to evaluate several modeling types (analytical and MCS) of the acquisition process of a pinhole SPECT system available at our institute. Secondly, various complexity degrees of an efficient and simplified analytical modeling of the physical effects occurring into the detector during SPECT examinations will be investigated. The two-developed analytical modeling of detector response represent some fast and efficient alternatives strategies to the implemented MCS based one. Although, even if they are less accurate, they allow coherent estimation while overcoming the disadvantages of the MCS like excessive computation time, high technical complexity and heavy computation infrastructures. However, the performance obtained, both qualitatively and quantitatively, do not allow their use in a quantitative reconstruction process. Nevertheless, recovery coefficient divergences with respect to the MCS reference modeling are on average of the order of ∼ 6%.

Over the last twenty years, PET systems have used discrete crystal detector modules coupled to multi-channel photodetectors, mostly to improve the spatial resolution. Although reading each readout channels individually would be of great interest, costs associated with the electronics would, in most cases, be too expensive. It is therefore essential to propose lower- cost solutions that do not degrade the overall system's performance. One possible solution to reduce the development costs of a PET system without degrading performance is the use of a resistive network which reduces the total number of readout channels. In this study, we present a symmetric charge division resistive network and associated software methods to assess the performance of a PET detector. Our approach consists in keeping the n lines and n columns information provided by a symmetric charge division circuit (SCD). We provided equations relative to output currents of the network, which enable estimation of the charge. We propose a novel approach to reconstruct the charge distribution from the lines and columns projection using a maximum likelihood expectation maximization (MLEM) approach which takes the non-uniformity of the photodetector channel gains into account. We also introduce a mathematical proof of the relation between the sigma of the reconstructed charge distribution and the Ratio between the line of interest (maximum value) and the background signal charges. To the best of our knowledge, this is the first study reporting these equations. Preliminary results obtained with a resistive network used in readout of a monolithic 50x50x8 mm(3) LYSO crystal coupled to a H9500 PMT validated the effectiveness of the reconstructed charge distribution to optimize both the x and y spatial resolution and the energy resolution. We obtained a mean x and y spatial resolution of 1.10 mm FWHM and a 14.7% energy resolution by calculating the integral of the reconstructed charge distribution. Finally, the relation between the ratio and the sigma of the reconstructed charge distribution may provide new opportunities in terms of Depth-of-Interaction estimation when using a monolithic crystal coupled to a multi-channel photodetector. (C) 2017 Elsevier B. V. All rights reserved.

Introduction: Herein we have evaluated the uptake of O-(2-F-18-fluoroethyl)-L-tyrosine (F-18-FET) in insulinoma in comparison with those of 6-F-18-fluoro-3,4-dihydroxy-L-phenylalanine (F-18-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia.Methods: Dynamic F-18-FET and carbidopa-assisted F-18-FDOPA PEI' were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test.Results: Seven and three nude mice bearing a RIN-m5F insulinoma xenograft were respectively studied by F-18-FET and F-18-FDOPA PET, Insulinoma xenograft was detected in all the imaged animals. Xenograft was characterized by an early but moderate increase of F-18-FET uptake followed by a slight decline of uptake intensity during the 20 min dynamic acquisition. Tumoral radiotracer peak intensity and the highest tumor-to-background contrast were reached about 5 minutes after F-18-FET iv. injection (mean SUV: 1.21 0.10). The biodistribution of F-18-FET and F-18-FDOPA and their dynamic tumoral uptake profile and intensity were similar. In the examined patient, F-18-FDOPA and F-18-FET PET/CT showed one concordant focal area of well-defined increased uptake in the pancreatic tail corresponding to 11 mm histologically proved insulinoma. The SUVmax tumor to liver ratio was 1.5,1.1 for F-18-FDOPA, 1.1,1 for F-18-FET at early (0-5 min post injection) and delayed (5-20 min post injection) PET/CT acquisition, respectively. Despite the relatively low tumoral uptake intensity, insulinoma was clearly identified due to the low background in the pancreas. At the contrary, no F-18-FDOPA or F-18-FET tumoral uptake was revealed on whole-body PET/CT images performed about 30 min after radiotracer administration. Note of worth, the dynamic uptake pattern of F-18-FET and F-18-FDOPA were similar between human insulinoma and mice xenograft tumor.Conclusion: F-18-FET PET compared equally to F-18-FDOPA PET in a preclinical RIN-m5F murine model of insulinoma and in one patient with insulinoma-related hypoglycemia. However, in both cases, the tumoral uptake intensity was moderate and the tumor was only visible until 20 min after radiotracer injection. Hence, caution should be taken before asserting the translational relevance of our results in the clinical practices. However, the structural analogies between 15F-FET and F-18-FDOPA as well as the limited pancreatic uptake of F-18-FET in human, encourage evaluating F-18-FET as diagnostic radiotracer for insulinoma detection in further prospective studies involving large cohorts of patients. (C) 2017 Elsevier Inc. All rights reserved.

Awake and/or freely moving small animal single photon emission imaging allows the continuous study of molecules exhibiting slow kinetics without the need to restrain or anaesthetise the animals. Estimating motion free projections in freely moving small animal planar imaging can be considered as a limited angle tomography problem, except that we wish to estimate the 2D planar projections rather than the 3D volume, where the angular sampling in all three axes depends on the rotational motion of the animal. In this study, we hypothesise that the motion corrected planar projections estimated by reconstructing an estimate of the 3D volume using an iterative motion compensating reconstruction algorithm and integrating it along the projection path, will closely match the true, motion-less, planar distribution regardless of the object motion. We tested this hypothesis for the case of rigid motion using Monte-Carlo simulations and experimental phantom data based on a dual opposed detector system, where object motion was modelled with 6 degrees of freedom. In addition, we investigated the quantitative accuracy of the regional activity extracted from the geometric mean of opposing motion corrected planar projections. Results showed that it is feasible to estimate qualitatively accurate motion-corrected projections for a wide range of motions around all 3 axes. Errors in the geometric mean estimates of regional activity were relatively small and within 10% of expected true values. In addition, quantitative regional errors were dependent on the observed motion, as well as on the surrounding activity of overlapping organs. We conclude that both qualitatively and quantitatively accurate motion-free projections of the tracer distribution in a rigidly moving object can be estimated from dual opposed detectors using a correction approach within an iterative reconstruction framework and we expect this approach can be extended to the case of non-rigid motion.

Nowadays, the use of gold standard Monte Carlo Simulation (MCS) based modeling of the acquisition process in a way to compute the System Matrix (SM) is one of the well-established methods that has been used in small animal SPECT image reconstruction. However, MCS requires extensive computation time to obtain a low noise SM. Such reconstruction methods are therefore largely penalized by the huge time consumption required for the SM generation since a large number of photons has to be generated: an improvement in simulation speed is thus mandatory. Simplified analytical approach has the potential to lead to efficient SM computation, in a reduced time while requiring neither particular computing skills nor heavy informatics resources (cluster). In this work, we proposed to evaluate several modeling types (analytical and MCS) of the acquisition process of a pinhole SPECT system available at our institute. Secondly, various complexity degrees of an efficient and simplified analytical modeling of the physical effects occurring into the detector during SPECT examinations will be investigated. The two-developed analytical modeling of detector response represent some fast and efficient alternatives strategies to the implemented MCS based one. Although, even if they are less accurate, they allow coherent estimation while overcoming the disadvantages of the MCS like excessive computation time, high technical complexity and heavy computation infrastructures. However, the performance obtained, both qualitatively and quantitatively, do not allow their use in a quantitative reconstruction process. Nevertheless, recovery coefficient divergences with respect to the MCS reference modeling are on average of the order of similar to 6%.