Dynamic Positron Emission Tomography Acquisition Research Articles

Data driven surrogate signal extraction for dynamic PET using selective PCA: time windows versus the combination of components

Objective. Respiratory motion correction is beneficial in positron emission tomography (PET), as it can reduce artefacts caused by motion and improve quantitative accuracy. Methods of motion correction are commonly based on a respiratory trace obtained through an external device (like the real time position management system) or a data driven method, such as those based on dimensionality reduction techniques (for instance principal component analysis (PCA)). PCA itself being a linear transformation to the axis of greatest variation. Data driven methods have the advantage of being non-invasive, and can be performed post-acquisition. However, their main downside being that they are adversely affected by the tracer kinetics of the dynamic PET acquisition. Therefore, they are mostly limited to static PET acquisitions. This work seeks to extend on existing PCA-based data-driven motion correction methods, to allow for their applicability to dynamic PET imaging. Approach. The methods explored in this work include; a moving window approach (similar to the Kinetic Respiratory Gating method from Schleyer et al (2014)), extrapolation of the principal component from later time points to earlier time points, and a method to score, select, and combine multiple respiratory components. The resulting respiratory traces were evaluated on 22 data sets from a dynamic [18F]-FDG study on patients with idiopathic pulmonary fibrosis. This was achieved by calculating their correlation with a surrogate signal acquired using a real time position management system. Main results. The results indicate that all methods produce better surrogate signals than when applying conventional PCA to dynamic data (for instance, a higher correlation with a gold standard respiratory trace). Extrapolating a late time point principal component produced more promising results than using a moving window. Scoring, selecting, and combining components held benefits over all other methods. Significance. This work allows for the extraction of a surrogate signal from dynamic PET data earlier in the acquisition and with a greater accuracy than previous work. This potentially allows for numerous other methods (for instance, respiratory motion correction) to be applied to this data (when they otherwise could not be previously used).

Abstract 13712: Imaging Short-Chain Fatty Acid Metabolism and Transport in the Failing Heart by PET

Introduction: Heart failure compromises the transport and oxidation of long chain fatty acids. Cardiomyocytes can compensate by using short-chain fatty acids (SCFA) which rely on other transport mechanisms. Based on this principle, we used 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), a radiolabeled SCFA analog, to assess these metabolic changes and image them by positron emission tomography (PET) in a doxorubicin-induced mouse model of cardiotoxicity. Hypothesis: We hypothesize that the increased demand for SCFA by the failing heart promotes cardiac accumulation of [ 18 F]FPA which can be imaged by PET. Methods: [ 18 F]FPA was injected intravenously into male C57BL/6J mice 10 weeks following intraperitoneal injections of 8 x 3 mg/kg doxorubicin (DOX). Dynamic PET acquisitions were performed from 60-120 min post injection of 9.25-11 MBq [ 18 F]FPA. These images were acquired in the presence or absence of 5 mg/kg AZD3965, an inhibitor of monocarboxylate transporters. Heart uptake of [ 18 F]FPA was determined by image-based quantitation and confirmed by a biodistribution study. Mechanistic [ 18 F]FPA uptake studies were also conducted in primary human cardiomyocyte (HCM) cultures. Results: Mice experiencing DOX-induced cardiotoxicity exhibited statistically significant increases in cardiac [ 18 F]FPA. AZD3965 did not significantly alter cardiac uptake but reduced uptake in all other tissues except the kidneys, the route of excretion. Additionally, [ 18 F]FPA uptake is lost in HCM for which mitochondrial acyl-CoA synthetase (ACSS) 1, but not cytosolic ACSS2, is inhibited. Conclusions: Our findings present both mechanistic and translational applications for [ 18 F]FPA. AZD3965 effectively reduced [ 18 F]FPA uptake in other tissues except for the heart and can therefore be co-administered to enhance the heart-to-background ratio. Altogether, our results indicate that [ 18 F]FPA may enter cardiac tissues by diffusion and become metabolically trapped in mitochondria.

Spatiotemporal Learning of Dynamic Positron Emission Tomography Data Improves Diagnostic Accuracy in Breast Cancer

Positron emission tomography (PET) is a noninvasive imaging technology able to assess the metabolic or functional state of healthy and/or pathological tissues. In clinical practice, PET data are usually acquired statically and normalized for the evaluation of the standardized uptake value (SUV). In contrast, dynamic PET acquisitions provide information about radiotracer delivery to tissue, its interaction with the target and its physiological washout. The shape of the time activity curves (TACs) embeds tissue-specific biochemical properties. Conventionally, TACs are employed along with information about blood plasma activity concentration, i.e., the arterial input function, and tracer-specific compartmental models to obtain a full quantitative analysis of PET data. This method’s primary disadvantage is the requirement for invasive arterial blood sample collection throughout the whole PET scan. In this study, we employ a variety of deep learning models to illustrate the diagnostic potential of dynamic PET acquisitions of varying lengths for discriminating breast cancer lesions in the absence of arterial blood sampling compared to static PET only. Our findings demonstrate that the use of TACs, even in the absence of arterial blood sampling and even when using only a share of all timeframes available, outperforms the discriminative ability of conventional SUV analysis.

Feasibility of using abbreviated scan protocols with population-based input functions for accurate kinetic modeling of [18F]-FDG datasets from a long axial FOV PET scanner

BackgroundAccurate kinetic modeling of 18F-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) data requires accurate knowledge of the available tracer concentration in the plasma during the scan time, known as the arterial input function (AIF). The gold standard method to derive the AIF requires collection of serial arterial blood samples, but the introduction of long axial field of view (LAFOV) PET systems enables the use of non-invasive image-derived input functions (IDIFs) from large blood pools such as the aorta without any need for bed movement. However, such protocols require a prolonged dynamic PET acquisition, which is impractical in a busy clinical setting. Population-based input functions (PBIFs) have previously shown potential in accurate Patlak analysis of [18F]-FDG datasets and can enable the use of shortened dynamic imaging protocols. Here, we exploit the high sensitivity and temporal resolution of a LAFOV PET system and explore the use of PBIF with abbreviated protocols in [18F]-FDG total body kinetic modeling.MethodsDynamic PET data were acquired in 24 oncological subjects for 65 min following the administration of [18F]-FDG. IDIFs were extracted from the descending thoracic aorta, and a PBIF was generated from 16 datasets. Five different scaled PBIFs (sPBIFs) were generated by scaling the PBIF with the AUC of IDIF curve tails using various portions of image data (35–65, 40–65, 45–65, 50–65, and 55–65 min post-injection). The sPBIFs were compared with the IDIFs using the AUCs and Patlak Ki estimates in tumor lesions and cerebral gray matter. Patlak plot start time (t*) was also varied to evaluate the performance of shorter acquisitions on the accuracy of Patlak Ki estimates. Patlak Ki estimates with IDIF and t* = 35 min were used as reference, and mean bias and precision (standard deviation of bias) were calculated to assess the relative performance of different sPBIFs. A comparison of parametric images generated using IDIF and sPBIFs was also performed.ResultsThere was no statistically significant difference between AUCs of the IDIF and sPBIFs (Wilcoxon test: P > 0.05). Excellent agreement was shown between Patlak Ki estimates obtained using sPBIF and IDIF. Using the sPBIF55–65 with the Patlak model, 20 min of PET data (i.e., 45 to 65 min post-injection) achieved < 15% precision error in Ki estimates in tumor lesions compared to the estimates with the IDIF. Parametric images reconstructed using the IDIF and sPBIFs with and without an abbreviated protocol were visually comparable. Using Patlak Ki generated with an IDIF and 30 min of PET data as reference, Patlak Ki images generated using sPBIF55–65 with 20 min of PET data (t* = 45 min) provided excellent image quality with structural similarity index measure > 0.99 and peak signal-to-noise ratio > 55 dB.ConclusionWe demonstrate the feasibility of performing accurate [18F]-FDG Patlak analysis using sPBIFs with only 20 min of PET data from a LAFOV PET scanner.

Spatiotemporal learning of dynamic positron emission tomography data improves diagnostic accuracy in breast cancer.

Positron emission tomography (PET) can reveal metabolic activity in a voxelwise manner. PET analysis is commonly performed in a static manner by analyzing the standardized uptake value (SUV) obtained from the plateau region of PET acquisitions. A dynamic PET acquisition can provide a map of the spatiotemporal concentration of the tracer in vivo, hence conveying information about radiotracer delivery to tissue, its interaction with the target and washout. Therefore, tissue-specific biochemical properties are embedded in the shape of time activity curves (TACs), which are generally used for kinetic analysis. Conventionally, TACs are employed along with information about blood plasma activity concentration, i.e., the arterial input function (AIF), and specific compartmental models to obtain a full quantitative analysis of PET data. The main drawback of this approach is the need for invasive procedures requiring arterial blood sample collection during the whole PET scan. In this paper, we address the challenge of improving PET diagnostic accuracy through an alternative approach based on the analysis of time signal intensity patterns. Specifically, we demonstrate the diagnostic potential of tissue TACs provided by dynamic PET acquisition using various deep learning models. Our framework is shown to outperform the discriminative potential of classical SUV analysis, hence paving the way for more accurate PET-based lesion discrimination without additional acquisition time or invasive procedures. Clinical Relevance- The diagnostic accuracy of dynamic PET data exploited by deep-learning based time signal intensity pattern analysis is superior to that of static SUV imaging.

The Value of FET PET/CT in Recurrent Glioma with a Different IDH Mutation Status: The Relationship between Imaging and Molecular Biomarkers

The evaluation of treatment response remains a challenge in glioma cases because the neuro oncological therapy can lead to the development of treatment-related changes (TRC) that mimic true progression (TP). Positron emission tomography (PET) using O-(2-[18F] fluoroethyl-)-L-tyrosine (18F-FET) has been shown to be a useful tool for detecting TRC and TP. We assessed the diagnostic performance of different 18F-FET PET segmentation approaches and different imaging biomarkers for differentiation between late TRC and TP in glioma patients. Isocitrate dehydrogenase (IDH) status was evaluated as a predictor of disease outcome. In our study, the proportion of TRC in IDH wild type (IDHwt) and IDH mutant (IDHm) subgroups was without significant difference. We found that the diagnostic value of static and dynamic biomarkers of 18F-FET PET for discrimination between TRC and TP depends on the IDH mutation status of the tumor. Dynamic 18F-FET PET acquisition proved helpful in the IDH wild type (IDHwt) subgroup, as opposed to the IDH mutant (IDHm) subgroup, providing an early indication to discontinue dynamic imaging in the IDHm subgroup.

18F-florbetapir PET/MRI for quantitatively monitoring myelin loss and recovery in patients with multiple sclerosis: A longitudinal study.

BackgroundAmyloid positron emission tomography (PET) can measure in-vivo demyelination in patients with multiple sclerosis (MS). However, the value of 18F-labeled amyloid PET tracer, 18F-florbetapir in the longitudinal study for monitoring myelin loss and recovery has not been confirmed.MethodsFrom March 2019 to September 2020, twenty-three patients with MS and nine healthy controls (HCs) underwent a hybrid PET/MRI at baseline and expanded disability status scale (EDSS) assessment, and eight of 23 patients further underwent follow-up PET/MRI. The distribution volume ratio (DVR) and standard uptake value ratio (SUVR) of 18F-florbetapir in damaged white matter (DWM) and normal-appearance white matter (NAWM) were obtained from dynamic and static PET acquisition. Diffusion tensor imaging-derived parameters were also calculated. Data were expressed as mean ± standard deviation with 99% confidence interval (99%CI).FindingThe mean DVR (1.08 ± 0.12, 99%CI [1.02 ~ 1.14]) but not the mean SUVR of DWM lesions was lower than that of NAWM in patients with MS (1.25 ± 0.10, 99%CI [1.20 ~ 1.31]) and HCs (1.29 ± 0.08, 99%CI [1.23 ~ 1.36]). A trend toward lower mean fractional anisotropy (374.95 ± 45.30 vs. 419.07 ± 4.83) and higher mean radial diffusivity (0.45 ± 0.05 vs. 0.40 ± 0.01) of NAWM in patients with MS than those in HCs was found. DVR decreased in DWM lesions with higher MD (rho = -0.261, 99%CI [-0.362 ~ -0.144]), higher AD (rho = -0.200, 99%CI [-0.318 ~ -0.070]) and higher RD (rho = -0.198, 99%CI [-0.313 ~ -0.075]). Patients’ EDSS scores were reduced (B = 0.04, 99%CI [-0.005 ~ 0.084]) with decreased index of global demyelination in the longitudinal study.InterpretationOur exploratory study suggests that dynamic 18F-florbetapir PET/MRI may be a very promising tool for quantitatively monitoring myelin loss and recovery in patients with MS.FundingShanghai Pujiang Program, Shanghai Municipal Key Clinical Specialty, Shanghai Shuguang Plan Project, Shanghai Health and Family Planning Commission Research Project, Clinical Research Plan of SHDC, French-Chinese program "Xu Guangqi".

1866-P: Adipocyte Hypertrophy Is Associated with Increased Dietary Fatty Acid Storage in Adipose Tissue and Reduced Postprandial Hepatic Fatty Acid Uptake and Esterification in Humans

Introduction: Excessive exposure of lean tissues to nonesterified fatty acids (NEFA) leads to insulin resistance (IR). Adipocyte hypertrophy is associated with IR and increase in adipose tissue intracellular triglyceride lipolysis and in NEFA levels, that may contribute to hepatic steatosis and IR. The effect of adipocyte hypertrophy on postprandial hepatic NEFA flux and metabolism and dietary fatty acids (DFA) storage in adipose tissues has not been studied, however. Methods: In 28 healthy adult subjects, fat cell size (FCS) was determined via histomorphologic analysis of abdominal subcutaneous fat tissue. Adipose tissue DFA storage was measured using oral administration of 18FTHA with positron emission tomography (PET). Postprandial hepatic NEFA uptake, oxidation, and esterification were determined using intravenous 11C-palmitate with dynamic PET acquisition. Results: As expected, FCS was correlated positively with fasting glycemia (ρ=0.44, P-value=0.029), homeostasis model assessment-estimated insulin resistance (HOMA-IR) (ρ=0.43, P-value=0.049), and hepatic fat content from CT radiodensity (ρ=0.32, P-value=0.10). FCS was correlated positively with DFA storage in intra-abdominal adipose tissues (ρ=0.48, P-value=0.022) and negatively with postprandial hepatic NEFA uptake (ρ=-0.42, P-value=0.027) and esterification (ρ=-0.58, P-value=0.0080). Conclusion: Adipocyte hypertrophy is associated with increased DFA storage in intra-abdominal adipose tissues and reduced postprandial hepatic NEFA uptake and esterification, despite being associated with greater hepatic fat content, fasting glycemia and HOMA-IR. Adipocyte hypertrophy is thus associated with adipose tissue metabolic adaptation that limits the exposure of the liver to fatty acids in the postprandial period. Disclosure R. Ye: None. S. Phoenix: None. C. Noll: None. E. Montastier: None. F. Frisch: None. L. Bouffard: None. M. Amrani: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc. Funding Canadian Institutes of Health Research (MOP53094); Centre de recherche du CHUS; Centre d’imagerie moléculaire de Sherbrooke; Faculté de médecine et des sciences de la santé de l’Université de Sherbrooke

PET [11C]acetate is also a perfusion tracer for kidney evaluation purposes

RationaleRenal positron emission tomography (PET) functional imaging allows non-invasive and dynamic measurements of functional and metabolic parameters. [15O]H2O is used as a perfusion tracer, and [11C]acetate as an oxidative metabolism in this purpose, requiring two injections to assess those fundamental parameters. Yet, in cardiac physiology study, the high first-pass myocardial extraction fraction of [11C]acetate allowed to use its influx rate as a blood flow marker too. Since [11C]acetate has been characterized by a 20–25% single pass renal extraction in dogs, it could be used as a potential tracer for renal perfusion. The aim of this study was to determine whether [11C]acetate influx rate can be used as quantitative in vivo marker of kidney perfusion in human. MethodsIn 10 healthy subjects, dynamic PET acquisitions were performed after [15O]H2O and [11C]acetate injections spaced by a 15-minute interval. As previously validated, with compartmental modeling of kinetics, renal perfusion and oxidative metabolism were estimated respectively with influx rate of [15O]H2O and efflux rate of [11C]acetate. Additionally, influx rate of [11C]acetate was regressed to influx rate of [15O]H2O. ResultsRenal time activity curves of [11C]-acetate was best fitted with a mono compartmental model compared to a bi-compartmental model (p < 0.0001). [11C]acetate influx rate was significantly correlated with perfusion quantified with [15O]H2O (r2 = 0.37, p < 0.001) at baseline. This regression allowed the computation of a renal [11C]acetate extraction fraction (EF), and further the computation of renal blood flow from its influx rate. ConclusionIn healthy subjects, over a wide range of renal perfusion, direct estimates of renal oxygen consumption as well as tissue perfusion can be obtained by PET with a single tracer [11C]acetate. This approach needs to be validated in CKD patients, and would be of great interest to design clinical protocol aiming at evaluating ischemic nephropathies candidate to revascularization.

How Long of a Dynamic 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) PET Acquisition Is Needed for Robust Kinetic Analysis in Breast Cancer?

To quantitatively evaluate the minimally required scanning time of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) dynamic acquisition for accurate kinetic assessment of the proliferation in breast cancer tumors. Within a therapeutic intervention trial, 26 breast tumors of 8 breast cancer patients were analyzed from 30-min dynamic [18F]FLT-PET acquisitions. PET/CT was acquired on a Gemini TF 64 system (Philips Healthcare) and reconstructed into 26 frames (8 × 15s, 6 × 30s, 5 × 1min, 5 × 2min, and 2 × 5min). Maximum activity concentrations (Bq/ml) of volume of interests over tumors and plasma in descending aorta were obtained over time frames. Kinetic parameters were estimated using in-house developed software with the two-tissue three-compartment irreversible model (2TCM) (K1, k2, k3, and Ki; k4 = 0) and Patlak model (Ki) based on different acquisition durations (Td) (10, 12, 14, 16, 20, 25, and 30min, separately). Different linear regression onset time (T0) points (1, 2, 3, 4, and 5min) were applied in Patlak analysis. Ki of the 30-min data set was taken as the gold standard for comparison. Pearson product-moment correlation coefficient (R) of 0.9 was chosen as a limit for the correlation. The correlation of kinetic parameters between the gold standard and the abbreviated dynamic data series increased with longer Td from 10 to 30min. k2 and k3 using 2TCM and Ki using Patlak model revealed poor correlations for dynamic PET with Td ≤ 14min (k2: R = 0.84, 0.85, 0.86; k3: R = 0.67, 0.67, 0.67; Ki: R = 0.72, 0.78, 0.87 at Td = 10, 12, and 14min, respectively). Excellent correlations were shown for all kinetic parameters when Td ≥ 16min regardless of the kinetic model and T0 value (R > 0.9). This study indicates that a 16-min dynamic PET acquisition appears to be sufficient to provide accurate [18F]FLT kinetics to quantitatively assess the proliferation in breast cancer lesions.

Hypoxia PET imaging techniques: data acquisition and analysis

Hypoxia is associated with poor treatment outcome in several tumor entities. Positron emission tomography (PET) offers the possibility to visualize tumor hypoxia in a spatially resolved manner using dedicated hypoxia PET tracers. The aim of this article is to review different tracers, PET acquisition methods and data analysis strategies that have been used in previous studies. A literature research has been performed in the database PubMed using the keywords “FMISO”, “FAZA”, “HX4”, “EF3/5” or “Cu-ATSM” in combination with “hypoxia”, “PET”, and “radiotherapy” in order to review the current status of hypoxia PET acquisition and data analysis strategies. A total of 141 articles were identified during the literature search. However, after exclusion of preclinical or simulation studies, 51 remained. Hypoxia PET imaging using different PET tracers was shown to have prognostic power in order to stratify patients according to outcome after chemoradiotherapy. However, most studies present small patient groups and use a variety of different PET acquisition protocols and data analysis strategies. Hypoxia PET acquisition can be performed using either static or dynamic PET acquisition. Due to the slow diffusive transport of the tracer, image acquisition needs to be performed several (2–4) h post-injection. Motivated by the low intrinsic contrast of hypoxia PET imaging, most studies use tumor-to-muscle ratios (TMR) to define areas of tumor hypoxia from static PET images, whereas dynamic scans are quantitatively analyzed using kinetic modeling. Data acquisition and analysis for hypoxia PET imaging requires standardization and harmonization, in order to empower large multicenter trials in the future, which are needed to proof the clinical benefit of personalized treatments on the basis of hypoxia PET imaging.

TU‐G‐BRA‐08: BEST IN PHYSICS (JOINT IMAGING‐THERAPY): Hybrid PET‐MRI Imaging of Acute Radiation Induced Cardiac Toxicity

Purpose:To identify the presence of low‐dose radiation induced cardiac toxicity in a canine model using hybrid positron emission tomography (PET) and magnetic resonance imaging (MRI).Methods:Research ethics board approval was obtained for a longitudinal imaging study of 5 canines after cardiac irradiation. Animals were imaged at baseline, 1 week post cardiac irradiation, and 1 month post cardiac irradiation using a hybrid PET‐ MRI system (Biograph mMR, Siemens Healthcare). The imaging protocol was designed to assess acute changes in myocardial perfusion and inflammation. Myocardial perfusion imaging was performed using N13‐ammonia tracer followed by a dynamic PET acquisition scan. A compartmental tracer kinetic model was used for absolute perfusion quantification. Myocardial inflammation imaging was performed using F18‐fluorodeoxyglucose (FDG) tracer. The standard uptake value (SUV) over a region encompassing the whole heart was used to compare FDG scans. All animals received a simulation CT scan (GE Medical Systems) for radiation treatment planning. Radiation treatment plans were created using the Pinncale3 treatment planning system (Philips Radiation Oncology Systems) and designed to resemble the typical cardiac exposure during left‐sided breast cancer radiotherapy. Cardiac irradiations were performed in a single fraction using a TrueBeam linear accelerator (Varian Medical Systems).Results:The delivered dose (mean ± standard deviation) to heart was 1.8±0.2 Gy. Reductions in myocardial stress perfusion relative to baseline were observed in 2 of the 5 animals 1 month post radiation. A global inflammatory response 1 month post radiation was observed in 4 of the 5 animals. The calculated SUV at 1 month post radiation was significantly higher (p=0.05) than the baseline SUV.Conclusion:Low doses of cardiac irradiation (&lt; 2 Gy) may lead to myocardial perfusion defects and a global inflammatory response that can be detectable as early as 1 month post irradiation using hybrid PET‐MRI imaging techniques.

Abstract 110: Preclinical evaluation of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide: A novel pyridazinoindole ligand for PET imaging of TSPO in cancer

Abstract There exists a continued need for the development of improved positron emission tomography (PET) biomarkers for glioma imaging to aid in tumor diagnosis, inform clinical outcome, and quantify response to therapeutic intervention. Translocator protein (TSPO) expression is elevated in cancer and has been linked with disease progression and diminished survival and tends to be a hallmark of aggressive tumors. Our laboratory has pursued development of TSPO PET ligands as candidates for molecular imaging of glioma, as TSPO ligand binding correlates with tumor grade in this setting. We report the first exploration of the structure-activity relationship (SAR) around the pyridazinoindole ring and subsequent radiofluorination of a potent and novel pyridazinoindole-based TSPO-selective ligand for cancer imaging. Library and SAR development around the N3 position of the pyridazinoindole scaffold led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (VUIIS8310), a novel TSPO ligand exhibiting a binding affinity comparable to SSR180575, yet bearing a fluorine atom for subsequent radiolabeling with fluorine-18 (18F) to give 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (18F-VUIIS8310). Initial production feasibility and radiochemical development were evaluated with microfluidics and subsequently translated to traditional box-based methods. Subsequently, quantitative, preclinical elevation of 18F-VUIIS8310 was conducted in a rat glioma model, given our previous experience in this setting. Glioma-bearing rats were imaged in a microPET system, with dynamic PET acquisitions acquired simultaneously upon tracer injection. PET ligand reversibility and specificity were evaluated by ligand displacement studies that utilized VUIIS8310. 18F-VUIIS8310 exhibited elevated uptake and specific, displaceable binding in tumor, in contrast with normal brain, which exhibited very low uptake. 18F-VUIIS8310 uptake in the tumor, relative to normal brain, reached a tumor-to-normal brain ratio of greater than 10:1. Ex vivo histological analysis of resected tissue correlated well with PET imaging data. These preclinical studies illuminate 18F-VUIIS8310 as a promising, novel TSPO PET ligand for imaging glioma and potentially other solid tumors. Importantly, the in vivo stability and high signal-to-noise achieved between tumor and surrounding normal brain suggest the potential of this PET ligand for early tumor detection within this setting. Future head-to-head comparisons between this tracer and emerging, potent TSPO ligands (J. Med. Chem. 2013, 56, 3429) are underway. Citation Format: Yiu-Yin Cheung, Jason R. Buck, Michael L. Nickels, Dewei Tang, H. Charles Manning. Preclinical evaluation of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide: A novel pyridazinoindole ligand for PET imaging of TSPO in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 110. doi:10.1158/1538-7445.AM2014-110

Deriving physiological information from PET images: from SUV to compartmental modelling

Positron emission tomography (PET) imaging has made it possible to detect the in vivo concentration of positron-emitting compounds accurately and non-invasively. In order to relate the radioactivity concentration measured using PET to the underlying physiological or biochemical processes, the application of mathematical models to describe tracer kinetics within a particular region of interest is necessary. Image analysis can be performed both by visual interpretation and quantitative assessment and, depending on the ultimate purposes of the analysis, several alternatives are available. In clinical practice, PET quantification is routinely performed using the standard uptake value (SUV), a semi-quantitative index in use since the 1980s. Its computation is very simple since it requires only the PET measure at a pre-fixed sample time and the injected dose normalised to some anthropometric characteristic of the subject (generally body weight or body surface area). An alternative to the SUV is the tissue-to-plasma ratio (ratio). As its name indicates, this index is computed as the ratio between the tracer activity measured in the tissue and in the plasma pool within a pre-fixed time window. Moving from static to more informative dynamic PET acquisition, three model classes represent the most frequently used approaches: compartmental models, the spectral analysis modelling approach, and graphical methods. These approaches differ in terms of application assumptions (e.g. reversibility of tracer uptake, model structure, etc.) and computational complexity. They also produce different information about the system under study: from a macro-description of tracer uptake to a full quantitative characterisation of the physiological processes in which the tracer is involved. The application of these approaches to clinical routine is restricted by the need for invasive blood sampling. In order to avoid arterial cannulation and blood sample management, different alternative approaches have been developed for quantification of PET kinetics, including reference tissue methods. Although these approaches are appealing, the results obtained with several tracers are questionable. This review provides a complete overview of the semi-quantitative and quantitative methods used in PET analysis. The pros and cons of each method are evaluated and discussed.

Dynamic PET/CT measurements of induced positron activity in a prostate cancer patient after 50-MV photon radiation therapy

BackgroundThe purpose of this work was to reveal the research interest value of positron emission tomography (PET) imaging in visualizing the induced tissue activity post high-energy photon radiation treatment. More specifically, the focus was on the possibility of retrieving data such as tissue composition and physical half-lives from dynamic PET acquisitions, as positron-emitting radionuclides such as 15O, 11C, and 13N are produced in vivo during radiation treatment with high-energy photons (>15 MeV). The type, amount, and distribution of induced positron-emitting radionuclides depend on the irradiated tissue cross section, the photon spectrum, and the possible perfusion-driven washout.MethodsA 62-year-old man diagnosed with prostate cancer was referred for palliative radiation treatment of the pelvis minor. A total dose of 8 Gy was given using high-energy photon beams (50 MV) with a racetrack microtron, and 7 min after the end of irradiation, the patient was positioned in a PET/computed tomography (CT) camera, and a list-mode acquisition was performed for 30 min. Two volumes of interests (VOIs) were positioned on the dynamic PET/CT images, one in the urinary bladder and the other in the subcutaneous fat. Analysis of the measured relative count rate was performed in order to compute the tissue compositions and physical half-lives in the two regions.ResultsDynamic analysis from the two VOIs showed that the decay constants of activated oxygen and carbon could be deduced. Calculation of tissue composition from analyzing the VOI containing subcutaneous fat only moderately agreed with that of the tabulated International Commission on Radiation Units & Measurements (ICRU) data of the adipose tissue. However, the same analysis for the bladder showed a good agreement with that of the tabulated ICRU data.ConclusionsPET can be used in visualizing the induced activity post high-energy photon radiation treatment. Despite the very low count rate in this specific application, wherein 7 min after treatment was about 5% of that of a standard 18F-FDG PET scan, the distribution of activated tissue elements (15O and 11C) could be calculated from the dynamic PET data. One possible future application of this method could possibly be to measure and determine the tumor tissue composition in order to identify any hypoxic or necrotic region, which is information that can be used in the ongoing therapy planning process.Trial registrationThe official name of the trial committee of this study is ‘Regionala etikprövningsnämnden i Stockholm’ (FE 289, Stockholm, SE-17177, Sweden). The unique identifying number is 2011/1789-31/2.

Quantitative dynamic 18FDG-PET and tracer kinetic analysis of soft tissue sarcomas

Purpose. To study soft tissue sarcomas using dynamic positron emission tomography (PET) with the glucose analog tracer [18F]fluoro-2-deoxy-D-glucose (18FDG), to investigate correlations between derived PET image parameters and clinical characteristics, and to discuss implications of dynamic PET acquisition (D-PET). Material and methods. D-PET images of 11 patients with soft tissue sarcomas were analyzed voxel-by-voxel using a compartment tracer kinetic model providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Furthermore, standard uptake values (SUVs) in the early (2 min p.i.; SUVE) and late (45 min p.i.; SUVL) phases of the PET acquisition were obtained. The derived transfer rates K1, k2 and k3, along with the metabolic rate of 18FDG (MRFDG) and the vascular fraction νp, was fused with the computed tomography (CT) images for visual interpretation. Correlations between D-PET imaging parameters and clinical parameters, i.e. tumor size, grade and clinical status, were calculated with a significance level of 0.05. Results. The temporal uptake pattern of 18FDG in the tumor varied considerably from patient to patient. SUVE peak was higher than SUVL peak for four patients. The images of the rate constants showed a systematic pattern, often with elevated intensity in the tumors compared to surrounding tissue. Significant correlations were found between SUVE/L and some of the rate parameters. Conclusions. Dynamic 18FDG-PET may provide additional valuable information on soft tissue sarcomas not obtainable from conventional 18FDG-PET. The prognostic role of dynamic imaging should be investigated.

Feasibility of 62Cu-ATSM PET for evaluation of brain ischaemia and misery perfusion in patients with cerebrovascular disease

[(62)Cu]Diacetyl-bis(N (4)-methylthiosemicarbazone) ((62)Cu-ATSM) was used to evaluate brain haemodynamic impairment in patients with cerebrovascular disease (CVD) as a simplified evaluation method. The tracer distribution was compared with haemodynamic parameters obtained by (15)O positron emission tomography (PET). Ten patients with major cerebral arterial occlusive disease (aged 66 ± 7 years) underwent PET with (62)Cu-ATSM and (15)O tracers ((15)O-water, (15)O(2) and C(15)O). Seven healthy volunteers also underwent (62)Cu-ATSM PET as normal controls. After the injection of (62)Cu-ATSM, 20-min dynamic PET data acquisition was started. Early- and delayed-phase images of (62)Cu-ATSM were obtained by averaging the initial 3-min and the last 10-min frame data, which were used for perfusion and retention images. Cerebral blood flow (CBF), blood volume, metabolic rate of oxygen (CMRO(2)) and oxygen extraction fraction (OEF) were measured by (15)O-gas and water studies and compared with early- and delayed-phase (62)Cu-ATSM images and delayed to early (D/E) ratio. Regional values were compared after all parametric images were coregistered to individual MRI. The asymmetry index (AI) was also calculated for OEF and Cu-ATSM D/E ratio, and diagnostic ability for detecting misery perfusion was compared. In the affected hemisphere of the patients, the mean values of haemodynamic parameters were CBF = 33.8 ± 5.9 ml/100 g per min, CMRO(2) = 2.6 ± 0.3 ml/100 g per min and OEF = 48 ± 7%. Standardized uptake values (SUVs) for (62)Cu-ATSM in early and delayed phases were 2.00 ± 0.13 and 1.04 ± 0.09 in the ipsilateral hemisphere and 2.13 ± 0.14 and 1.04 ± 0.08 in the contralateral hemisphere, respectively. The early-phase (62)Cu-ATSM images corresponded well to CBF images, and the D/E ratio images were similar to OEF images. Regional values obtained from D/E ratio images were significantly correlated with regional OEF. AIs of OEF and D/E ratio showed a significant correlation and diagnostic ability of misery perfusion was slightly better in AI of D/E ratio than that of OEF. Dynamic PET acquisition with (62)Cu-ATSM provided information on CBF distribution and local elevation of OEF in patients with chronic CVD. The findings of the present study showed the feasibility of the noninvasive molecular imaging method for diagnosing misery perfusion with a single venous tracer injection.

Non-invasive assessment of skeletal kinetics using fluorine-18 fluoride positron emission tomography: evaluation of image and population-derived arterial input functions.

To measure regional skeletal kinetics using fluorine-18 fluoride positron emission tomography (PET) it is necessary to know the concentration of radioactive tracer being delivered to bone by arterial plasma with relation to time, the arterial input function (IFa). Methods by which IFa can be derived without arterial sampling are attractive because of their relative technical simplicity and the reduction in possible morbidity to the subject. We have compared the use of a scaled population input function (IFp) and a corrected image-derived input function from the aorta (IFi) with an IFa directly measured from a radial artery line in ten normal postmenopausal women. Both of the aforementioned methods rely only on a small number of discrete venous samples. Each subject had a dynamic PET acquisition of the lumbar spine performed after the intravenous injection of 180 MBq (18)F-fluoride. Both the IFp and the IFi were compared with the IFa in terms of the accuracy of determination of six parameters. These were: plasma clearance of fluoride to bone mineral (K(i)), unidirectional plasma clearance to total bone tissue (K(1)) and individual rate constants k(2), k(3) and k(4), calculated using non-linear regression with a three-compartment model, and the plasma clearance to bone mineral calculated using the Patlak method (K(pat)). For both the IFp and the IFi method the root mean square errors for K(pat) and K(i) were similar and small (<8.2%). The errors in determining K(1) and the rate constants k(2) to k(4) are larger by either method, but with a small advantage using the IFp method. It is concluded that the use of either non-invasive method for determining the arterial plasma input function is suitable for the measurement of the most important parameters, K(i) and K(pat), in these subjects.