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Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [18F]SynVesT-1 for preclinical applications. In C57Bl/6J mice (n = 39), we assessed the plasma profile of [18F]SynVesT-1, validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function (AIF), performed a blocking study with levetiracetam (50 and 200 mg/kg, i.p.) to verify the specificity towards SV2A, examined kinetic models for volume of distribution (V T) quantification, and explored test-retest reproducibility of [18F]SynVesT-1 in the central nervous system (CNS). Plasma availability of [18F]SynVesT-1 decreased rapidly (13.4 ± 1.5% at 30 min post-injection). V T based on AIF and IDIF showed excellent agreement (r2 = 0.95, p < 0.0001) and could be reliably estimated with a 60-min acquisition. The blocking study resulted in a complete blockade with no suitable reference region. Test-retest analysis indicated good reproducibility (mean absolute variability <10%). In conclusion, [18F]SynVesT-1 is selective for SV2A with optimal kinetics representing a candidate tool to quantify CNS synaptic density non-invasively. [ABSTRACT FROM AUTHOR]

A maximum likelihood reconstruction algorithm for gated dynamic cardiac PET studies was developed and evaluated. A two dimensional tensor product spline basis spanning the time and gate domain is proposed. The activity variations introduced by the biochemical kinetics and cardiac motion are modeled as conic combinations of the B-spline basis functions. The basis explicitly takes the cyclic nature of the heart motion into account. We make use of the expectation-maximization (EM) algorithm to derive a closed form iteration scheme for the reconstruction. The proposed algorithm is validated through computer simulations of the dynamic NCAT beating heart phantom and the kinetics of [sup.13]N-ammonia uptake. We used the Monte Carlo simulator GATE to simulate a typical PET scanner. We qualitatively found that a reconstruction using cubic splines resulted in smoother images while better delineating the myocardial wall. Fourth order spline modeling reduced the mean squared error (MSE) of binned reconstruction by 56% whereas conventional Gaussian filtering reduced the MSE by 38%. Spline modeling in the gate domain reduced the MSE by 72 % compared to a reduction of 47 % obtained with filtering. Quantitative evaluation of the reconstructed motion information suggested that the number of basis functions in the gate domain could be reduced from 16 in a framed approach to 5 for reconstructions using a higher order spline interpolation. Index Terms--Dynamic and gated PET, myocardium, tensor product splines.

A theoretical formulation of the effective point spread function of a slat collimator on a strip detector has been derived. The used technique to obtain the geometric transfer function, which is the Fourier transform of the effective point source image, is based on the geometric characteristics of a single gap and it accurately describes the performance of the collimation system for system analysis. Valuable conclusions resulting from this geometric transfer function could be made on the sensitivity, on the spatial resolution, and on the line spread function of the imaging system. We found that the sensitivity was dependent on the angle of incidence and on the distance to the detector. The spatial resolution was constant in a plane at a fixed distance to the detector and closed analytical expressions were derived for transaxial line spread profiles. These results were confirmed by the appropriate Monte Carlo simulations. The presented formulation of the geometric transfer function will be useful with usage in iterative reconstruction algorithms to incorporate distance dependent effects. Index Terms--Effective point spread function, geometric transfer function, resolution, sensitivity, solstice.

Nonuniform patient attenuation maps can be acquired using an axially moving point source of a high energy isotope that emits a fanbeam of photons. We simulated the Beacon attenuation correction tool attached to multiheaded Single Photon Emission Computed Tomography (SPECT) cameras which uses this approach. We investigated the scatter order of the photons reaching the detector, and the scatter contributions from the different detector components were evaluated for different energy windows. In case of simultaneous emission and transmission scanning the spatial signals are electronically windowed to allow differentiation between photons from the attenuation and from the emission source. However, an additional correction needs to be applied for cross-contamination. When applying the Beacon device in hybrid mode [gammacamera-Positron Emission Tomography (PET)] there are no degrees of freedom for crystal and collimator. The inter-window contamination was thus examined in detail to derive possible protocol optimizations for that dedicated setup. For the case of applying Beacon-SPECT, we performed multiple types of simulations including different crystal thicknesses and different collimators to evaluate the inter-window contamination. The main conclusion of this work is that a thick crystal detector coupled to a Low Energy High Resolution (LEHR) collimator is the best solution for acquiring attenuation maps in low energy applications. For medium energy studies attenuation maps have to be rescaled to account for the low sensitivity near the center of the patient. Fully Monte Carlo simulating the system matrix for medium energy studies on low energy collimators in order to replace the Medium Energy General Purpose (MEGP) collimators by the LEHR variants appeared to be a more valuable approach. This last method is penalized by a computational burden but results in an improved image quality after reconstruction. Index Terms--Beacon, Geant4 Application for Tomographic Emission (GATE), transmission imaging.

Abstract Background The increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest of scientific research in this field. Therefore, a vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma (HCC) in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for HCC research, in which tumours develop in a natural background of fibrosis and (2) to assess the time-dependent angiogenic changes in the pathogenesis of HCC. Methods Weekly intraperitoneal injections with the hepatocarcinogenic compound N-nitrosodiethylamine was applied as induction method and samples were taken at several time points to assess the angiogenic changes during the progression of HCC. Results The N-nitrosodiethylamine-induced mouse model provides well vascularised orthotopic tumours after 25 weeks. It is a representative model for human HCC and can serve as an excellent platform for the development of new therapeutic targets.

Depending on the molar activity of the tracer, the maximal allowable injected activity in mouse brain PET studies can be extremely low in order to avoid receptor saturation. Therefore, a high level of noise can be present in the image. We investigate several dynamic PET reconstruction methods in reduced counts, or equivalently in reduced injected activity, data exemplified in [11C]raclopride BPND and quantification using the simplified reference tissue model (SRTM). We compared independent frame reconstruction (IFR), post-reconstruction HYPR denoising (IFR + HYPR), direct reconstruction using the SRTM model (DIR-SRTM), and the spatial (KERS) and spatiotemporal kernel reconstruction (KERST). Additionally, HYPR denoising of the frames used as features for the calculation of the spatial kernel matrix, was investigated (KERS-HYPR and KERST-HYPR). In vivo data of 11 mice, was used to generate list-mode data for five reduced count levels corresponding to reductions by a factor 4, 8, 12, 16 and 32 (equivalently 2.07, 1.04, 0.691, 0.518, and 0.260 MBq). Correlation of regional BPND and values (reduced versus full counts reconstructions) was high (r > 0.94) for all methods, with KERS-HYPR and KERST-HYPR reaching the highest correlation (r > 0.96). Among methods with regularization, DIR-SRTM showed the largest variability in BPND (Bland–Altman SD from 3.0% to 12%), while IFR showed it for (5.1%–14.6%). KERST and KERST-HYPR were the only methods with Bland–Altman bias and SD below 5% for noise level up to a reduction factor of 16. At the voxel level, BPND and correlation was gradually decreased with increasing noise, with the largest correlation (BPNDr > 0.88, r > 0.62) for KERS-HYPR and KERST-HYPR. The spatial and the spatiotemporal kernel methods performed similarly, while using only temporal regularization with direct reconstruction showed more variability. Although R1 values present noise, using the spatiotemporal kernel reconstruction, accurate estimates of binding potential could be obtained with mouse injected activities as low as 0.26–0.518 MBq. This is desirable in order to maintain the tracer kinetics principle in mouse studies. [ABSTRACT FROM AUTHOR]

We investigated the potential use of [18F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. Methods. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [18F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUVmax) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. Results. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUVmax (Δ SUVmax). For all treatments combined, Δ SUVmax after 2 days was predictive for RTV after 7 days (r = 0.69 , p = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (− 30 % ± 10 % and − 20 % ± 20 % , respectively) and Δ SUVmax (− 39 % ± 36 % and − 42 % ± 8 % , respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and Δ SUVmax decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, Δ SUVmax after 2 days was predictive for RTV after 7 days (r = 0.48 , p = 0.028), but the correlation could be improved when combination with everolimus (r = 0.59 , p = 0.023) or trastuzumab (r = 0.69 , p = 0.015) was excluded. Conclusion. Reduction in [18F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [18F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [18F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways. [ABSTRACT FROM AUTHOR]

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. V T (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K 1 (IDIF). A scan duration of 60 min was sufficient for reliable V T (IDIF) and K 1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models. [ABSTRACT FROM AUTHOR]