Whole-body Dynamic PET Research Articles

First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues

PurposeMultidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer’s and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues.MethodsThirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h− 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology.ResultsMean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h− 1 (− 4 ± 24%), cerebellum: 0.033 ± 0.009 h− 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h− 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h− 1 (30 ± 38%), lungs: 0.875 ± 0.095 h− 1 (− 3 ± 11%), myocardium: 0.641 ± 0.105 h− 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h− 1 (14 ± 16%), and liver: 0.685 ± 0.072 h− 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women.ConclusionLAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans.Trial registrationEudraCT 2021-006348-29. Registered 15 December 2021.

Test-Retest Repeatability of Patlak Slopes versus Standardized Uptake Values for Hypermetabolic Lesions and Normal Organs in an Oncologic PET/CT Population.

We aimed to determine the test-retest repeatability of quantitative metrics based on the Patlak slope (PS) versus the standardized uptake value (SUV) among lesions and normal organs on oncologic [18F]FDG-PET/CT. This prospective, single-center study enrolled adults undergoing standard-of-care oncologic [18F]FDG-PET/CTs. Early (35-50min post-injection) and late (75-90min post-injection) SUV and PS images were reconstructed from dynamic whole-body PET data. Repeat imaging occurred within 7days. Relevant quantitative metrics were extracted from lesions and normal organs. Repeatability was assessed via mean test-retest percent changes [T-RT %Δ], within-subject coefficients of variation (wCVs), and intra-class correlation coefficients (ICCs). Nine subjects (mean age, 61.7 ± 6.2years; 6 females) completed the test-retest protocol. Four subjects collectively had 17 [18F]FDG-avid lesions. Lesion wCVs were higher (i.e., worse repeatability) for PS-early-max (16.2%) and PS-early-peak (15.6%) than for SUV-early-max (8.9%) and SUV-early-peak (8.1%), with similar early metric ICCs (0.95-0.98). Lesion wCVs were similar for PS-late-max (8.5%) and PS-late-peak (6.4%) relative to SUV-late-max (9.7%) and SUV-late-peak (7.2%), with similar late metric ICCs (0.93-0.98). There was a significant bias toward higher retest SUV and PS values in the lesion analysis (T-RT %Δ [95% CI]: SUV-late-max, 10.0% [2.6%, 17.0%]; PS-late-max, 20.4% [14.3%, 26.4%]) but not in the normal organ analysis. Among [18F]FDG-avid lesions, the repeatability of PS-based metrics is similar to equivalent SUV-based metrics at late post-injection time points, indicating that PS-based metrics may be suitable for tracking response to oncologic therapies. However, further validation is required in light of our study's limitations, including small sample size and bias toward higher retest values for some metrics.

Improvement of motion artifacts using dynamic whole-body 18F-FDG PET/CT imaging

PurposeSerial dynamic whole-body PET imaging is valuable for assessing serial changes in tracer uptake. The purpose of this study was to evaluate the improvement of motion artifacts in patients using serial dynamic whole-body 18F-fluorodeoxyglyucose (FDG) PET/CT imaging.Materials and methodsIn 797 consecutive patients, serial 3-min dynamic whole-body FDG PET imaging was performed seven times, at 60 or 90 min after FDG administration. In cases with large body motion during imaging, we tried to improve the images by summing the images before body motion. An image quality study was performed on another 50 patients without obvious body motion using the same acquisition mode.ResultsObvious body movement was observed in 106 of 797 cases (13.3%), and severe motion artifacts which interfered image interpretation were observed in 18 (2.3%). In these 18 cases, summation of the images before the body movement enabled us to obtain images that excluded the effect of the body motion. In the visual evaluation of the image quality in another 50 patients studied, acceptable image quality was obtained when 2 or more times the serial 3-min image data were added.ConclusionSerial dynamic whole-body FDG PET imaging can minimize body motion artifacts by summation of the images before the body motion. Such serial dynamic study may be a choice for PET imaging to eliminate motion artifacts.

Immuno-PET of colorectal cancer with a CEA-targeted [68Ga]Ga-nanobody: from bench to bedside.

An accurate diagnosis of colorectal carcinoma (CRC) can assist physicians in developing reasonable therapeutic regimens, thereby significantly improving the patient's prognosis. Carcinoembryonic antigen (CEA)-targeted PET imaging shows great potential for this purpose. Despite showing remarkable abilities to detect primary and metastatic CRC, previously reported CEA-specific antibody radiotracers or pretargeted imaging are not suitable for clinical use due to poor pharmacokinetics and complicated imaging procedures. In contrast, radiolabeled nanobodies exhibit ideal characteristics for PET imaging, for instance, rapid clearance rates and excellent distribution profiles, allowing same-day imaging with sufficient contrast. In this study, we developed a novel CEA-targeted nanobody radiotracer, [68Ga]Ga-HNI01, and assessed its tumor imaging ability and biodistribution profile in preclinical xenografts and patients with primary and metastatic CRC. The novel nanobody HNI01 was acquired by immunizing the llama with CEA proteins. [68Ga]Ga-HNI01 was synthesized by site-specifically conjugating [68Ga]Ga with tris(hydroxypyridinone) (THP). Small-animal PET imaging and biodistribution studies were performed in CEA-overexpressed LS174T and CEA-low-expressed HT-29 tumor models. Following successful preclinical assessment, a phase I study was conducted on 9 patients with primary and metastatic CRC. Study participants received 151.21 ± 25.25MBq of intravenous [68Ga]Ga-HNI01 and underwent PET/CT scans at 1h and 2h post injection. Patients 01-03 also underwent whole-body dynamic PET imaging within 0-40min p.i. All patients underwent [18F]F-FDG PET/CT imaging within 1week after [68Ga]Ga-HNI01 imaging. Tracer distribution, pharmacokinetics, and radiation dosimetry were calculated. [68Ga]Ga-HNI01 was successfully synthesized within 10min under mild conditions, and the radiochemical purity was more than 98% without purification. Micro-PET imaging with [68Ga]Ga-HNI01 revealed clear visualization of LS174T tumors, while signals from HT-29 tumors were significantly lower. Biodistribution studies indicated that uptake of [68Ga]Ga-HNI01 in LS174T and HT-29 was 8.83 ± 3.02%ID/g and 1.81 ± 0.87%ID/g, respectively, at 2h p.i. No adverse events occurred in all clinical participants after the injection of [68Ga]Ga-HNI01. A fast blood clearance and low background uptake were observed, and CRC lesions could be visualized with high contrast as early as 30min after injection. [68Ga]Ga-HNI01 PET could clearly detect metastatic lesions in the liver, lung, and pancreas and showed superior ability in detecting small metastases. A significant accumulation of radioactivity was observed in the kidney, and normal tissues physiologically expressing CEA receptors showed slight uptakes of [68Ga]Ga-HNI01. An interesting finding was that strong uptake of [68Ga]Ga-HNI01 was found in non-malignant colorectal tissues adjacent to the primary tumor in some patients, suggesting abnormal CEA expression in these healthy tissues. [68Ga]Ga-HNI01 is a novel CEA-targeted PET imaging radiotracer with excellent pharmacokinetics and favorable dosimetry profiles. [68Ga]Ga-HNI01 PET is an effective and convenient imaging tool for detecting CRC lesions, particularly for identifying small metastases. Furthermore, its high specificity for CEA in vivo makes it an ideal tool for selecting patients for anti-CEA therapy.

Diagnostic Performance of Dynamic Whole-Body Patlak [18F]FDG-PET/CT in Patients with Indeterminate Lung Lesions and Lymph Nodes.

Static [18F]FDG-PET/CT is the imaging method of choice for the evaluation of indeterminate lung lesions and NSCLC staging; however, histological confirmation of PET-positive lesions is needed in most cases due to its limited specificity. Therefore, we aimed to evaluate the diagnostic performance of additional dynamic whole-body PET. A total of 34 consecutive patients with indeterminate pulmonary lesions were enrolled in this prospective trial. All patients underwent static (60 min p.i.) and dynamic (0-60 min p.i.) whole-body [18F]FDG-PET/CT (300 MBq) using the multi-bed-multi-timepoint technique (Siemens mCT FlowMotion). Histology and follow-up served as ground truth. Kinetic modeling factors were calculated using a two-compartment linear Patlak model (FDG influx rate constant = Ki, metabolic rate = MR-FDG, distribution volume = DV-FDG) and compared to SUV using ROC analysis. MR-FDGmean provided the best discriminatory power between benign and malignant lung lesions with an AUC of 0.887. The AUC of DV-FDGmean (0.818) and SUVmean (0.827) was non-significantly lower. For LNM, the AUCs for MR-FDGmean (0.987) and SUVmean (0.993) were comparable. Moreover, the DV-FDGmean in liver metastases was three times higher than in bone or lung metastases. Metabolic rate quantification was shown to be a reliable method to detect malignant lung tumors, LNM, and distant metastases at least as accurately as the established SUV or dual-time-point PET scans.

Inter-pass motion correction for whole-body dynamic PET and parametric imaging.

Whole-body dynamic FDG-PET imaging through continuous-bed-motion (CBM) mode multi-pass acquisition protocol is a promising metabolism measurement. However, inter-pass misalignment originating from body movement could degrade parametric quantification. We aim to apply a non-rigid registration method for inter-pass motion correction in whole-body dynamic PET. 27 subjects underwent a 90-min whole-body FDG CBM PET scan on a Biograph mCT (Siemens Healthineers), acquiring 9 over-the-heart single-bed passes and subsequently 19 CBM passes (frames). The inter-pass motion correction was executed using non-rigid image registration with multi-resolution, B-spline free-form deformations. The parametric images were then generated by Patlak analysis. The overlaid Patlak slope Ki and y-intercept Vb images were visualized to qualitatively evaluate motion impact and correction effect. The normalized weighted mean squared Patlak fitting errors (NFE) were compared in the whole body, head, and hypermetabolic regions of interest (ROI). In Ki images, ROI statistics were collected and malignancy discrimination capacity was estimated by the area under the receiver operating characteristic curve (AUC). After the inter-pass motion correction was applied, the spatial misalignment appearance between Ki and Vb images was successfully reduced. Voxel-wise normalized fitting error maps showed global error reduction after motion correction. The NFE in the whole body (p = 0.0013), head (p = 0.0021), and ROIs (p = 0.0377) significantly decreased. The visual performance of each hypermetabolic ROI in Ki images was enhanced, while 3.59% and 3.67% average absolute percentage changes were observed in mean and maximum Ki values, respectively, across all evaluated ROIs. The estimated mean Ki values had substantial changes with motion correction (p = 0.0021). The AUC of both mean Ki and maximum Ki after motion correction increased, possibly suggesting the potential of enhancing oncological discrimination capacity through inter-pass motion correction.

Dosimetry and efficacy of a tau PET tracer [18F]MK-6240 in Japanese healthy elderly and patients with Alzheimer’s disease

ObjectiveA new tau PET tracer [18F]MK-6240 has been developed; however, its dosimetry and pharmacokinetics have been published only for a European population. This study investigated the safety, radiation dosimetry, pharmacokinetics and biodistribution of [18F]MK-6240 in Japanese elderly subjects. Also, the pattern and extent of brain retention of [18F]MK-6240 in Japanese healthy elderly subjects and patients with Alzheimer’s disease (AD) were investigated. These Japanese results were compared with previous reports on non-Japanese.MethodsThree healthy elderly subjects and three AD patients were enrolled. Dynamic whole-body PET scans were acquired for up to 232 min after starting injection of [18F]MK-6240 (370.4 ± 27.0 MBq) for the former, while a dynamic brain scan was performed from 0 to 75 min post injection for the latter. For both groups, brain PET scans were conducted from 90 to 110 min post injection. Sequential venous blood sampling was performed to measure the radioactivity concentration in the whole blood and plasma as well as the percentages of parent [18F]MK-6240 and radioactive metabolites in plasma. Organ doses and effective doses were estimated using the OLINDA Ver.2 software. Standardized uptake value ratios (SUVRs) and distribution volume ratios (DVRs) by Logan reference tissue model (LRTM) were measured in eight brain regions using the cerebellar cortex as the reference. Blood tests, urine analysis, vital signs and electrocardiography were performed for safety assessments.ResultsNo adverse events were observed. The highest radiation doses were received by the gallbladder (257.7 ± 74.9 μGy/MBq) and the urinary bladder (127.3 ± 11.7 μGy/MBq). The effective dose was 26.8 ± 1.4 μSv/MBq. The parent form ([18F]MK-6240) was metabolized quickly and was less than 15% by 35 min post injection. While no obvious accumulation was found in the brain of healthy subjects, focal accumulation of [18F]MK-6240 was observed in the cerebral cortex of AD patients. Regional SUVRs of the focal lesions in AD patients increased gradually over time, and the difference of SUVRs between healthy subjects and AD patients became large and stable at 90 min after injection. High correlations of SUVR and DVR were observed (p < 0.01).ConclusionThe findings supported safety and efficacy of [18F]MK-6240 as a tau PET tracer for Japanese populations. Even though the number of subjects was limited, the radiation dosimetry profiles, pharmacokinetics, and biodistribution of [18F]MK-6240 were consistent with those for non-Japanese populations.Trial registrationJapan Pharmaceutical Information Center ID, JapicCTI-194972.

Role of dynamic and parametric whole-body FDG PET/CT imaging in molecular characterization of primary breast cancer: a single institution experience.

The aim of this pilot study was to assess the role of dynamic whole-body PET and parametric imaging in the biological characterization of primary breast cancer. In total 24 histologically proven primary breast cancer lesions in 21 consecutive patients were retrospectively analyzed. Each patient underwent 18F-fluoro-deoxyglucose whole-body dynamic PET-CT before any treatment. Dynamic PET images were acquired in the list mode for a total duration of 70 min. The reconstructed parametric imaging generated Patlak plot-based 'Slope' and 'Intercept' images, from which parametric indices ki and DV were obtained. The standard uptake value (SUV) metric was also obtained by summing the last few frames of the dynamic study. ki, distribution volume (DV) and SUV were correlated with the histological tumor grade, biomarkers [hormone receptors and human epidermal growth factor receptor 2 (HER-2) neu expression] and molecular subtypes (A, B and C) as well as with tumor size, regional nodal metastases and distant metastases. The mean ki was found to be significantly higher in grade III than II lesions (P = 0.005), HER-2 neu positive status (P = 0.04) and molecular subtype B (P = 0.04) as well as in greater than T1 lesions(P = 0.0003 and P = 0.04, respectively) and node-positive lesions (P = 0.009). Though mean ki was not found to be significant for the hormone receptors status (P = 0.08), it showed the best correlation compared to the other parameters (P = 0.8 for DV and P = 0.1 for SUV). Spearman's correlation test, area under the curve (AUC) and mismatch percentage also revealed ki to predict tumor grade (AUC, 0.95; r = 0.7; P = 0.0001), HER-2 neu status and molecular subtypes (AUC, 0.81; r = 0.49 and P = 0.01) along with the hormone receptors status (AUC, 0.83; r = 0.32; P = 0.1). The mean DV failed to show any association with any of the biological or anatomical staging parameters. Though ki was found to be comparable to that of SUV in almost all the assessed parameters, it appeared to be better for predicting hormone receptors status even though both parameters were not statistically significant. Our initial observation in a small cohort of breast cancer patients suggests that ki is promising in stratifying primary breast cancer lesions according to the tumor grade and biological characteristics.

Unsupervised inter-frame motion correction for whole-body dynamic PET using convolutional long short-term memory in a convolutional neural network.

Subject motion in whole-body dynamic PET introduces inter-frame mismatch and seriously impacts parametric imaging. Traditional non-rigid registration methods are generally computationally intense and time-consuming. Deep learning approaches are promising in achieving high accuracy with fast speed, but have yet been investigated with consideration for tracer distribution changes or in the whole-body scope. In this work, we developed an unsupervised automatic deep learning-based framework to correct inter-frame body motion. The motion estimation network is a convolutional neural network with a combined convolutional long short-term memory layer, fully utilizing dynamic temporal features and spatial information. Our dataset contains 27 subjects each under a 90-min FDG whole-body dynamic PET scan. Evaluating performance in motion simulation studies and a 9-fold cross-validation on the human subject dataset, compared with both traditional and deep learning baselines, we demonstrated that the proposed network achieved the lowest motion prediction error, obtained superior performance in enhanced qualitative and quantitative spatial alignment between parametric Ki and Vb images, and significantly reduced parametric fitting error. We also showed the potential of the proposed motion correction method for impacting downstream analysis of the estimated parametric images, improving the ability to distinguish malignant from benign hypermetabolic regions of interest. Once trained, the motion estimation inference time of our proposed network was around 460 times faster than the conventional registration baseline, showing its potential to be easily applied in clinical settings.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 μg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Simplified protocol for whole-body Patlak parametric imaging with 18 F-FDG PET/CT: Feasibility and error analysis.

Parametric imaging using the Patlak model has been shown to provide improved lesion detectability and specificity. The Patlak model requires both tissue time-activity curves (TACs) after equilibrium and knowledge of the input function from the start of injection. Therefore, the conventional dynamic scanning protocol typically starts from the radiotracer injection all the way to equilibrium. In this paper, we propose the use of hybrid population-based and model-based input function estimation and evaluate its use for whole-body Patlak analysis, in order to reduce the total scan time and simplify clinical Patlak parametric imaging protocols. Possible quantitative errors caused by the simplified scanning protocol were also analyzed both theoretically and with the use of clinical data. Clinical data from 24 patients referred for tumor staging were included in this study. The patients underwent a whole-body dynamic PET study, 20min after FDG injection (0.13mCi/kg). The proposed whole-body scanning protocol includes 6 passes with 4-5 bed positions, depending on the size of the patient, with 2min for each bed position. An input function from the literature was selected as the shape of the population-based input function. The descending aorta from the corresponding CT image was segmented and applied on the reconstructed dynamic PET images to acquire an image-based input function, which was later fitted using an exponential model. Due to the late scan time, only the later portion of the input function was available, which was used to scale the population-based input function. The hybrid input function was used to derive the whole-body Patlak images. Assuming a given error in the population-based input function, its influence on the final Patlak images were also derived theoretically and verified using the clinical data sets. Finally, the image quality of the reconstructed Patlak slope image was evaluated by an experienced radiologist in four different aspects: image artifacts, image noise, lesion sharpness, and lesion detectability. It was found that errors in the population-based input function only affect the absolute scale of the Patlak slope image. The induced error is proportional to the percentage area-under-curve (AUC) error in the input function. These findings were also confirmed by numerical analysis. The predicted global scale was in good agreement with results from both image-based Patlak and direct Patlak approach. The fractions of the AUC from the early portion population-based input function were also found to be around 18% of the total AUC of the input function, further limiting the propagation of quantitation error from population-based input function to the final Patlak slope image. The reconstructed Patlak images were also found by the radiologist to provide excellent confidence in lesion detection tasks. We have proposed a simplified whole-body scanning protocol that utilizes both population-based input function and model-based input function. The error from the population-based function was found to only affect the global scale and the overall quantitative impact can be predicted using our proposed formulas.

PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. MethodsSynthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. ResultsWe succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 μSv/MBq (range 5.2–5.7). ConclusionNovel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

Assessment of Lesion Detectability in Dynamic Whole-Body PET Imaging Using Compartmental and Patlak Parametric Mapping.

Hybrid dynamic imaging allows not only the estimation of whole-body (WB) macroparametric maps but also the estimation of microparameters in the initial bed position targeting the blood pool region containing the pathology owing to the limited axial field of view of PET scanners. In this work, we assessed the capability of multipass WB F-FDG PET parametric imaging in terms of lesion detectability through qualitative and quantitative evaluation of simulation and clinical studies. Simulation studies were conducted by generating data incorporating 3 liver and 3 lung lesions produced by 3 noise levels and 20 noise realizations for each noise level to estimate bias and lesion detection features. The total scan time for the clinical studies of 8 patients addressed for lung and liver lesions staging, including dynamic and static WB imaging, lasted 80 minutes. An in-house-developed MATLAB code was utilized to derive the microparametric and macroparametric maps. We compared lesion detectability and different image-derived PET metrics including the SUVs, Patlak-derived influx rate constant (Ki) and distribution volume (V) and K1, k2, k3, blood volume (bv) microparameters, and Ki estimated using the generalized linear least square approach. In total, 104 lesions were detected, among which 47 were located in the targeted blood pool bed position where all quantitative parameters were calculated, thus enabling comparative analysis across all parameters. The evaluation encompassed visual interpretation performed by an expert nuclear medicine specialist and quantitative analysis. High correlation coefficients were observed between SUVmax and Kimax derived from the generalized linear least square approach, as well as Ki generated by Patlak graphical analysis. Moreover, 3 contrast-enhanced CT-proven malignant lesions located in the liver and a biopsy-proven malignant liver lesion not visible on static SUV images and Patlak maps were clearly pinpointed on K1 and k2 maps. Our results demonstrate that full compartmental modeling for the region containing the pathology has the potential of providing complementary information and, in some cases, more accurate diagnosis than conventional static SUV imaging, favorably comparing to Patlak graphical analysis.

Dynamic whole-body 18F-FDG PET for differentiating abnormal lesions from physiological uptake.

Serial assessment of visual change in 18F-FDG uptake on whole-body 18F-FDG PET imaging was performed to differentiate pathological uptake from physiological uptake in the urinary and gastrointestinal tracts. In 88 suspected cancer patients, serial 3-min dynamic whole-body PET imaging was performed four times, from 60min after 18F-FDG administration. In dynamic image evaluation, high 18F-FDG uptake was evaluated by two nuclear medicine physicians and classified as "changed" or "unchanged" based on change in uptake shape over time. Detectability of pathological uptake based on these criteria was assessed and compared with conventional image evaluation. Dynamic whole-body PET imaging provided images of adequate quality for visual assessment. Dynamic image evaluation was "changed" in 118/154 regions of high physiological 18F-FDG uptake (77%): in 9/19 areas in the stomach (47%), in 32/39 in the small intestine (82%), in 17/33 in the colon (52%), and in 60/63 in the urinary tract (95%). In the 86 benign or malignant lesions, 84 lesions (98%) were "unchanged." A high 18F-FDG uptake area that shows no change over time using these criteria is highly likely to represent pathological uptake, with sensitivity of 97%, specificity of 76%, PPV of 70%, NPV of 98%, and accuracy of 84%. Dynamic whole-body 18F-FDG PET imaging enabled differentiation of pathological uptake from physiological uptake in the urinary and gastrointestinal tracts, based on visual change of uptake shape.

49 Evaluation and optimisation of parametric reconstruction algorithms in FDG PET imaging

Introduction. Recently there has been an increased interest in whole-body dynamic PET protocols for parametric imaging, for better diagnosis and prognosis in oncology. The aim of this study is to evaluate and optimise dynamic (4D) reconstruction algorithms as opposed to standard static (3D) reconstruction algorithms for improved quantification and image quality of glucose metabolic rate parametric images for FDG PET data.

One-pot synthesis and biodistribution of fluorine-18 labeled serum albumin for vascular imaging

IntroductionEquilibrium single-photon radionuclide imaging methods for assessing cardiac function and the integrity of the vascular system have long been in use for both clinical and research purposes. However, positron-emitting blood pool agents that could provide PET equivalents to these (and other) clinical procedures have not yet been adopted despite technical imaging advantages offered by PET. Our goal was to develop a PET blood pool tracer that not only meets necessary in vivo biological requirements but can be produced with an uncomplicated and rapid synthesis method which would facilitate clinical translation. Herein, albumin labeled with fluorine-18 was synthesized using a one-pot method and evaluated in vitro and in vivo in rats. MethodsA ligand (NODA-Bz-TFPE), containing NODA attached to a tetrafluorophenylester (TFPE) via a phenyl linker (Bz), was labeled with aluminum fluoride (Al[18F]F). Conjugation of the serum albumin with the ligand (Al[18F]F-NODA-Bz-TFPE), followed by purification (size exclusion chromatography), yielded the final product (Al[18F]F-NODA-Bz-RSA/HSA). In vitro stability was evaluated in human serum albumin by HPLC. Rat biodistributions and whole-body PET imaging over a 4 h time course were used for the in vivo evaluation. ResultsThis synthesis exhibited an overall radiochemical yield of 45 ± 10% (n = 30), a 50-min radiolabeling time, a radiochemical purity >99% and apparent stability up to 4 h in human serum. Blood had the highest retention of Al[18F]F-NODA-Bz-RSA at all times with a blood half-life of 5.2 h in rats. Al[18F]F-NODA-Bz-RSA distribution in most rat tissues remained relatively constant for up to 1 h, indicating that the tissue radioactivity content represents the respective tissue plasma volume. Dynamic whole-body PET images were in agreement with these findings. ConclusionsA new ligand has been developed and radiolabeled with Al[18F]F that allows rapid (50-min) preparation of fluorine-18 serum albumin in one-pot. In addition to increased synthetic efficiency, the construct appears to be metabolically stable in rats. This method could encourage wider use of PET to quantify cardiac function and tissue vascular integrity in both research and clinical settings.

Quantitative PET image reconstruction employing nested expectation-maximization deconvolution for motion compensation

Bulk body motion may randomly occur during PET acquisitions introducing blurring, attenuation-emission mismatches and, in dynamic PET, discontinuities in the measured time activity curves between consecutive frames. Meanwhile, dynamic PET scans are longer, thus increasing the probability of bulk motion. In this study, we propose a streamlined 3D PET motion-compensated image reconstruction (3D-MCIR) framework, capable of robustly deconvolving intra-frame motion from a static or dynamic 3D sinogram. The presented 3D-MCIR methods need not partition the data into multiple gates, such as 4D MCIR algorithms, or access list-mode (LM) data, such as LM MCIR methods, both associated with increased computation or memory resources. The proposed algorithms can support compensation for any periodic and non-periodic motion, such as cardio-respiratory or bulk motion, the latter including rolling, twisting or drifting. Inspired from the widely adopted point-spread function (PSF) deconvolution 3D PET reconstruction techniques, here we introduce an image-based 3D generalized motion deconvolution method within the standard 3D maximum-likelihood expectation-maximization (ML-EM) reconstruction framework. In particular, we initially integrate a motion blurring kernel, accounting for every tracked motion within a frame, as an additional MLEM modeling component in the image space (integrated 3D-MCIR). Subsequently, we replaced the integrated model component with a nested iterative Richardson-Lucy (RL) image-based deconvolution method to accelerate the MLEM algorithm convergence rate (RL-3D-MCIR). The final method was evaluated with realistic simulations of whole-body dynamic PET data employing the XCAT phantom and real human bulk motion profiles, the latter estimated from volunteer dynamic MRI scans. In addition, metabolic uptake rate Ki parametric images were generated with the standard Patlak method. Our results demonstrate significant improvement in contrast-to-noise ratio (CNR) and noise-bias performance in both dynamic and parametric images. The proposed nested RL-3D-MCIR method is implemented on the Software for Tomographic Image Reconstruction (STIR) open-source platform and is scheduled for public release.

Whole-body dynamic imaging with continuous bed motion PET/CT.

Most dynamic imaging protocols require long scan times that are beyond the range of what can be supported in a routine clinical environment and suffer from various difficulties related to step and shoot imaging techniques. In this short communication, we describe continuous bed motion (CBM) imaging techniques to create clinically relevant 15 min whole-body dynamic PET imaging protocols. We also present initial data that suggest that these CBM methods may be sufficient for quantitative analysis of uptake rates and rates of glucose metabolism. Multipass CBM PET was used in conjunction with a population-based input function to perform Patlak modeling of normal tissue. Net uptake rates were estimated and metabolic rates of glucose were calculated. Estimations of k3 (Ki/Vd) were calculated along with modeling of liver regions of interest to assess model stability. Calculated values of metabolic rates of glucose were well within normal ranges found in the previous literature. CBM techniques can potentially be used clinically to obtain reliable, quantitative multipass whole-body dynamic PET data. Values calculated for normal brain were shown to be within previously published values for normal brain glucose metabolism.

Clinical Translation of an Albumin-Binding PET Radiotracer 68Ga-NEB.

Suitably labeled Evans blue dye has been successfully applied to evaluate cardiac function, vascular permeability, and lymphatic imaging in preclinical settings. This study documented the first-in-human application of 68Ga-1,4,7-triazacyclononane-N,N',N″-triacetic acid (NOTA)-NEB. The NOTA-conjugated truncated form of Evans blue, NEB, was labeled with 68Ga and tested in BALB/C mice for dynamic PET and ex vivo biodistribution studies. Three healthy volunteers (2 men and 1 woman) underwent 90-min whole-body dynamic PET. The absorbed doses for major organs and whole body were calculated using OLINDA/EXM software. Eleven patients with focal hepatic lesions diagnosed by enhanced CT or MR imaging were subjected to whole-body PET/CT acquisitions at 30 min after intravenous injection of 111-148 MBq (3-4 mCi) of 68Ga-NEB. NEB dye was labeled with 68Ga (half-time, 68 min) with high yield and purity. After intravenous injection, 68Ga-NEB formed a complex with serum albumin, thus most of the radioactivity was retained in blood circulation. The tracer was demonstrated to be safe in both healthy volunteers and recruited patients without side effects or allergies. Among the 11 patients, hemangiomas showed much higher 68Ga-NEB signal intensity than the surrounding normal hepatic tissues, whereas no apparent difference between lesions and hepatic tissues was identified on 18F-FDG PET. All other focal hepatic lesions including hepatocellular carcinoma, hepatic cysts, and neuroendocrine tumor liver metastases showed negative 68Ga-NEB contrast to hepatic tissues. As a blood-pool imaging agent, 68Ga-NEB is safe to use in the clinic, and our preliminary studies demonstrate the value of differentiating hepatic hemangioma from other benign or malignant focal hepatic lesions. Easy labeling with different positron emitters of various half-lives, excellent pharmacokinetics, and imaging quality warrant further clinical applications of NEB-based PET tracers.

Dynamic whole-body PET parametric imaging: I. Concept, acquisition protocol optimization and clinical application

Static whole-body PET/CT, employing the standardized uptake value (SUV), is considered the standard clinical approach to diagnosis and treatment response monitoring for a wide range of oncologic malignancies. Alternative PET protocols involving dynamic acquisition of temporal images have been implemented in the research setting, allowing quantification of tracer dynamics, an important capability for tumor characterization and treatment response monitoring. Nonetheless, dynamic protocols have been confined to single-bed-coverage limiting the axial field-of-view to ∼15–20 cm, and have not been translated to the routine clinical context of whole-body PET imaging for the inspection of disseminated disease. Here, we pursue a transition to dynamic whole-body PET parametric imaging, by presenting, within a unified framework, clinically feasible multi-bed dynamic PET acquisition protocols and parametric imaging methods. We investigate solutions to address the challenges of: (i) long acquisitions, (ii) small number of dynamic frames per bed, and (iii) non-invasive quantification of kinetics in the plasma. In the present study, a novel dynamic (4D) whole-body PET acquisition protocol of ∼45 min total length is presented, composed of (i) an initial 6 min dynamic PET scan (24 frames) over the heart, followed by (ii) a sequence of multi-pass multi-bed PET scans (six passes × seven bed positions, each scanned for 45 s). Standard Patlak linear graphical analysis modeling was employed, coupled with image-derived plasma input function measurements. Ordinary least squares Patlak estimation was used as the baseline regression method to quantify the physiological parameters of tracer uptake rate Ki and total blood distribution volume V on an individual voxel basis. Extensive Monte Carlo simulation studies, using a wide set of published kinetic FDG parameters and GATE and XCAT platforms, were conducted to optimize the acquisition protocol from a range of ten different clinically acceptable sampling schedules examined. The framework was also applied to six FDG PET patient studies, demonstrating clinical feasibility. Both simulated and clinical results indicated enhanced contrast-to-noise ratios (CNRs) for Ki images in tumor regions with notable background FDG concentration, such as the liver, where SUV performed relatively poorly. Overall, the proposed framework enables enhanced quantification of physiological parameters across the whole body. In addition, the total acquisition length can be reduced from 45 to ∼35 min and still achieve improved or equivalent CNR compared to SUV, provided the true Ki contrast is sufficiently high. In the follow-up companion paper, a set of advanced linear regression schemes is presented to particularly address the presence of noise, and attempt to achieve a better trade-off between the mean-squared error and the CNR metrics, resulting in enhanced task-based imaging.