PET-MR Imaging Research Articles

Completely non-invasive prediction of IDH mutation status based on preoperative native CT images.

The isocitrate dehydrogenase (IDH) mutation status is one of the most important markers according to the 2021 WHO classification of CNS tumors. Preoperatively, this information is usually obtained based on invasive biopsies, contrast-enhanced MR images or PET images generated using radioactive tracers. However, the completely non-invasive determination of IDH mutation status using routinely acquired preoperative native CT images has hardly been investigated to date. In our study, we show that radiomics-based machine learning allows to determine IDH mutation status based on preoperative native CT images both with very high accuracy and completely non-invasively. Based on independent test data, we are able to correctly identify 91.1% of cases with an IDH mutation. Our final model, containing only six features, exhibits a high area under the curve of 0.847 and an excellent area under the precision-recall curve of 0.945. In the future, such models may be used for a completely non-invasive prediction of important genetic markers, potentially allowing treating physicians to reduce the number of biopsies and speed up further treatment planning.

Initial results of the Hyperion IIDPET insert for simultaneous PET-MRI applied to atherosclerotic plaque imaging in New-Zealand white rabbits.

In preclinical research, in vivo imaging of mice and rats is more
common than any other animal species, since their physiopathology is very well-
known and many genetically altered disease models exist. Animal studies based on
small rodents are usually performed using dedicated preclinical imaging systems
with high spatial resolution. For studies that require animal models such as mini-
pigs or New-Zealand White (NZW) rabbits, imaging systems with larger bore
sizes are required. In case of hybrid imaging using Positron Emission Tomography
(PET) and Magnetic Resonance Imaging (MRI), clinical systems have to be used,
as these animal models do not typically fi t in preclinical simultaneous PET-MRI
scanners.
Approach. In this paper, we present initial imaging results obtained with the
Hyperion IID PET insert which can accommodate NZW rabbits when combined
with a large volume MRI RF coil. First, we developed a rabbit-sized image
quality phantom of comparable size to a NZW rabbit in order to evaluate the
PET imaging performance of the insert under high count rates. For this phantom,
radioactive spheres with inner diameters between 3.95 and 7.86 mm were visible
in a warm background with a tracer activity ratio of 4.1 to 1 and with a total
18-F activity in the phantom of 58MBq at measurement start. Second, we performed
simultaneous PET-MR imaging of atherosclerotic plaques in a rabbit in vivo using
a single injection containing 18-F-FDG for detection of infl ammatory activity,
and Gd-ESMA for visualization of the aortic vessel wall and plaques with MRI.
Main results. The fused PET-MR images reveal 18-F-FDG uptake within an
active plaques with plaque thicknesses in the sub-millimeter range. Histology
showed colocalization of 18-F-FDG uptake with macrophages in the aortic vessel wall lesions. 
Significance. Our initial results demonstrate that this PET insert
is a promising system for simultaneous high-resolution PET-MR atherosclerotic
plaque imaging studies in NZW rabbits.

Phenotyping in vivo chronic inflammation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7T susceptibility-weighted imaging.

11C-PBR28 positron emission tomography (PET), targeting the translocator protein, and paramagnetic rim lesions (PRL) have emerged as promising imaging markers of MS chronic inflammation. No consensus on which is the optimal marker exists. To investigate the ability of 11C-PBR28 PET and PRL assessment to identify chronic inflammation in white matter (WM) MS lesions and their relation to neurological impairment. Based on 11C-PBR28 uptake, brain WM lesions from 30 MS patients were classified as PET active or inactive. The PRL presence was assessed on 7T phase reconstructions, T1/T2 ratio was calculated to measure WM microstructural integrity. Less than half (44%) of non-PRL WM lesions were active on 11C-PBR28 imaging either throughout the lesion (whole active) or at its periphery. PET peripherally active lesions and PRL did not differ in T1/T2 ratio and 11C-PBR28 uptake. A positive correlation was observed between PRL and active PET lesion count. Whole active PET lesion volume was the strongest predictor (β = 0.97, p < 0.001) of increased Expanded Disability Status Scale scores. 11C-PBR28 imaging reveals more active WM lesions than 7T PRL assessment. Although PRL and PET active lesion counts are related, neurological disability is better explained by PET whole active lesion volume.

Characterization of a Syngeneic Orthotopic Model of Cholangiocarcinoma by [18F]FDG-PET/MRI.

Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [18F]FDG-PET, and dynamic [18F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies.

Late Life Depression is Not Associated With Alzheimer-Type Tau: Preliminary Evidence From a Next-Generation Tau Ligand PET-MR Study

To investigate whether tau accumulation is higher in late life depression (LLD) compared to non-depressed cognitively unimpaired (CU) older adults. To situate these findings in the neurodegeneration model of LLD by assessing group differences in tau and grey matter volume (GMV) between LLD, non-depressed CU and mild cognitive impairment due to Alzheimer's Disease (MCI). Monocentric, cross-sectional study. University Psychiatric hospital, memory clinic and outpatient neurology practice. A total of 102 adults over age 60, of whom 19 currently depressed participants with LLD, 19 with MCI and 36 non-depressed CU participants completed neuropsychological testing and tau PET-MR imaging. PET-MRI: 18F-MK-6240 tracer SUVR for tau assessment; 3D T1-weighted structural MRI derived GMV in seven brain regions (temporal, cingulate, prefrontal and parietal regions); amyloid PET to assess amyloid positivity; Neuropsychological test scores: MMSE, RAVLT, GDS, MADRS. ANCOVA and Spearman's rank correlations to investigate group differences in tau and GMV, and correlations with neuropsychological test scores respectively. Compared to non-depressed CU participants, LLD patients showed lower GMV in temporal and anterior cingulate regions but similar tau accumulation and amyloid positivity rate. In contrast, MCI patients had significantly higher tau accumulation in all regions. Tau did not correlate with any neuropsychological test scores in LLD. Our findings suggest AD-type tau is not higher in LLD compared to non-depressed, cognitively unimpaired older adults and appears unlikely to contribute to lower gray matter volume in LLD, further underscoring the need to distinguish major depressive disorder from depressive symptoms occurring in early AD.

Initial clinical experience with the first-in-class anti-metastasis therapeutic TTX-MC138.

e15072 Background: TransCode is focused on developing nucleic acid-based cancer therapies. Through scientific discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. This knowledge allowed development of a therapeutic strategy based on miR-10b inhibition. miR-10b was targeted using antagomirs delivered to metastatic sites by an iron oxide nanocarrier, termed TTX-MC138. Results demonstrated that TTX-MC138 could cause complete and persistent regressions of metastases in cancer models. Methods: TransCode has an active eIND and is conducting a Phase 0 clinical study with radiolabeled TTX-MC138 in patients with advanced metastatic cancer of multiple tissue origins. TTX-MC138 was radiolabeled with Cu64 through a NODAGA chelator. IND enabling studies were conducted in rats and non-human primates to support FDA activation (eIND163800) for the Phase 0 clinical study. In the trial, a single intravenous microdose of Cu-64 labeled TTX-MC138 is administered, which allows for direct visualization of drug tissue distribution in cancer patients via PET-MR imaging. Results: Non-clinical studies were conducted to support the TTX-MC138 clinical development program. In rats, when TTX-MC138 was infused intravenously at a dose of 27 mg/kg, results displayed a blood half-life of 16.7±9.35 hrs. At 24-h, concentrations were highest in the liver and spleen. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation). RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. A study in rats involved a single injection with 0, 0.5 or 1 mg/kg followed by a 2-day or 14-day observational period. The drug was well-tolerated at levels up to 1 mg/kg, which was considered to be the no-observed-adverse-effect-level (NOAEL). Preliminary results from the Phase 0 clinical study showed that the first patient tolerated the dosing with no reported adverse reactions, the drug remained stable in circulation, and circulated with a long half-life of 20 hours. Lesion to blood ratios of radioactivity in the region of the metastatic lesions was consistent with accumulation of TTX-MC138. Enrollment, data monitoring, and analysis is ongoing. Conclusions: The results of the non-clinical studies and Phase 0 clinical study have the potential to address the question of delivery to the target tissue. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical trial information: NCT05908773 .

Abstract 4180: Evaluation of CD38 pharmacodynamics in multiple myeloma using PET with a Ga-68 labelled peptide

Abstract Introduction: Multiple myeloma (MM) is a disease of plasma cells that primarily arises in the bone marrow. CD38 is a receptor expressed uniformly and with high density in MM. Several CD38 targeted therapeutics are in clinic for MM. However, how those therapeutics engage or modulate CD38 is poorly understood particularly in lesions that cannot be assessed with routine blood testing. CD38 specific radiotracers for positron emission tomography (PET) could be helpful for detection of MM and for assessing therapy response early by measuring CD38 pharmacodynamics non-invasively. Here, we report the development of a first-in-class peptide-based PET radiotracer, [68Ga]AJ206, evaluation of its pharmacokinetics (PK), specificity for non-invasive CD38 detection, and its potential to evaluate therapy induced CD38 pharmacodynamics in mouse models of MM. Methods: A bicyclic peptide, AJ206, was synthesized and its binding affinity for CD38 was determined by surface plasmon resonance. AJ206 was labelled with Gallium-68 in high radiochemical yields and purity. In vitro uptake of [68Ga]AJ206 was carried out in four MM cell lines with variable CD38 expression (MOLP8, MM1S, RPMI8226, and U266). PK and biodistribution of [68Ga]AJ206 were evaluated by PET in cell line derived xenografts, in patient derived xenografts (PDXs) and in a disseminated disease model. PET data was corroborated by ex vivo biodistribution studies. [68Ga]AJ206 in vivo specificity for CD38 was confirmed by co-injection of non-radioactive AJ206 (1 mg/kg) and cross-correlative immunohistochemistry (IHC) of matched xenografts. Furthermore, ability of [68Ga]AJ206 to quantify CD38 pharmacodynamics was established by treating PDX models with all-trans retinoic acid (ATRA) and cross validating PET imaging observations with IHC. Results: AJ206 exhibits high affinity (KD,19 nM) for human CD38. In vitro binding assays showed variable [68Ga]AJ206 uptake in MM cells that correlated with receptor density measured by flow cytometry. Dynamic PET-MR imaging revealed high and specific uptake of [68Ga]AJ206 in MOLP8 tumor within 5 min that retained for at least 90 min. In contrast, [68Ga]AJ206 exhibited rapid clearance from normal tissues providing high contrast images at 60 minutes and a high tumor-to-muscle ratio of 27.1±2.7. Tumor uptake was reduced by &amp;gt; 80 % in mice receiving blocking dose, confirming the specificity of the radiotracer. Also, [68Ga]AJ206 could detect CD38 expression in different MM xenografts, PDXs and disseminated disease models which was corroborated by flow cytometry and IHC findings. Moreover, [68Ga]AJ206 successfully quantified the increased CD38 expression in PDXs following ATRA treatment. Conclusion: [68Ga]AJ206 is a CD38 specific high affinity peptide-based PET imaging agent that can be used to non-invasively quantify CD38 pharmacodynamics in MM, with potential applications in other diseases with CD38 involvement. Citation Format: Ajay Kumar Sharma, Kuldeep Gupta, Akhilesh Mishra, Gabriela Lofland, Ian Marsh, Dhiraj Kumar, Gabriel Ghiaur, Philip Imus, Steven P. Rowe, Robert Hobbs, Christian B. Gocke, Sridhar Nimmagadda. Evaluation of CD38 pharmacodynamics in multiple myeloma using PET with a Ga-68 labelled peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4180.

Clinical Arterial Spin-Labeling MR Imaging to Screen for Typical and Atypical Neurodegenerative Disease in the New Era of Alzheimer Treatment.

The clinical standard of care in the diagnosis of neurodegenerative diseases relies on [18F] FDG-PET/CT or PET MR imaging. Limitations of FDG-PET include cost, the need for IV access, radiation exposure, and availability. Arterial spin-labeling MR imaging has been shown in research settings to be useful as a proxy for FDG-PET in differentiating Alzheimer disease from frontotemporal dementia. However, it is not yet widely used in clinical practice, except in cerebrovascular disease. Here, we present 7 patients, imaged with our routine clinical protocol with diverse presentations of Alzheimer disease and other neurodegenerative diseases, in whom arterial spin-labeling-derived reduced CBF correlated with hypometabolism or amyloid/tau deposition on PET. Our case series illustrates the clinical diagnostic utility of arterial spin-labeling MR imaging as a fast, accessible, and noncontrast screening tool for neurodegenerative disease. Arterial spin-labeling MR imaging can guide patient selection for subsequent PET or fluid biomarker work-up, as well as for possible therapy with antiamyloid monoclonal antibodies.

The role of 18F-FDG PET in minimizing variability in gross tumor volume delineation of soft tissue sarcomas

BackgroundAccurate gross tumor volume (GTV) delineation is a critical step in radiation therapy treatment planning. However, it is reader dependent and thus susceptible to intra- and inter-reader variability. GTV delineation of soft tissue sarcoma (STS) often relies on CT and MR images. PurposeThis study investigates the potential role of 18F-FDG PET in reducing intra- and inter-reader variability thereby improving reproducibility of GTV delineation in STS, without incurring additional costs or radiation exposure. Materials and MethodsThree readers performed independent GTV delineation of 61 patients with STS using first CT and MR followed by CT, MR, and 18F-FDG PET images. Each reader performed a total of six delineation trials, three trials per imaging modality group. Dice Similarity Coefficient (DSC) score and Hausdorff distance (HD) were used to assess both intra- and inter-reader variability using generated simultaneous truth and performance level estimation (STAPLE) GTVs as ground truth. Statistical analysis was performed using a Wilcoxon signed-ranked test. ResultsThere was a statistically significant decrease in both intra- and inter-reader variability in GTV delineation using CT, MR 18F-FDG PET images vs. CT and MR images. This was translated by an increase in the DSC score and a decrease in the HD for GTVs drawn from CT, MR and 18F-FDG PET images vs. GTVs drawn from CT and MR for all readers and across all three trials. ConclusionIncorporation of 18F-FDG PET into CT and MR images decreased intra- and inter-reader variability and subsequently increased reproducibility of GTV delineation in STS.

Non-rigid motion-compensated 3D whole-heart T2 mapping in a hybrid 3T PET-MR system.

Simultaneous PET-MRI improves inflammatory cardiac disease diagnosis. However, challenges persist in respiratory motion and mis-registration between free-breathing 3D PET and 2D breath-held MR images. We propose a free-breathing non-rigid motion-compensated 3D T2 -mapping sequence enabling whole-heart myocardial tissue characterization in a hybrid 3T PET-MR system and provides non-rigid respiratory motion fields to correct also simultaneously acquired PET data. Free-breathing 3D whole-heart T2 -mapping was implemented on a hybrid 3T PET-MRI system. Three datasets were acquired with different T2 -preparation modules (0, 28, 55 ms) using 3-fold undersampled variable-density Cartesian trajectory. Respiratory motion was estimated via virtual 3D image navigators, enabling multi-contrast non-rigid motion-corrected MR reconstruction. T2 -maps were computed using dictionary-matching. Approach was tested in phantom, 8 healthy subjects, 14 MR only and 2 PET-MR patients with suspected cardiac disease and compared with spin echo reference (phantom) and clinical 2D T2 -mapping (in-vivo). Phantom results show a high correlation (R2 = 0.996) between proposed approach and gold standard 2D T2 mapping. In-vivo 3D T2 -mapping average values in healthy subjects (39.0 ± 1.4 ms) and patients (healthy tissue) (39.1 ± 1.4 ms) agree with conventional 2D T2 -mapping (healthy = 38.6 ± 1.2 ms, patients = 40.3 ± 1.7 ms). Bland-Altman analysis reveals bias of 1.8 ms and 95% limits of agreement (LOA) of -2.4-6 ms for healthy subjects, and bias of 1.3 ms and 95% LOA of -1.9 to 4.6 ms for patients. Validated efficient 3D whole-heart T2 -mapping at hybrid 3T PET-MRI provides myocardial inflammation characterization and non-rigid respiratory motion fields for simultaneous PET data correction. Comparable T2 values were achieved with both 3D and 2D methods. Improved image quality was observed in the PET images after MR-based motion correction.

Kiosk 5R-TB-07 - Hybrid PET-MR Imaging to Assess Acute Cardiovascular Changes in Response to Thoracic Radiotherapy and Chemotherapy in Cancer Patients

Kiosk 5R-TB-07 - Hybrid PET-MR Imaging to Assess Acute Cardiovascular Changes in Response to Thoracic Radiotherapy and Chemotherapy in Cancer Patients

The development of a generative approach for joint super-resolution image reconstruction from highly sparse raw data in the context of MR-PET imaging

The present study introduces a rapid and efficient approach for reconstructing high-resolution images in hybrid MRI-PET scanners. The application of sparsity, compressed sensing (CS), and super-resolution reconstruction (SRR) methodologies can significantly decrease the demands of data acquisition while concurrently attaining high-resolution output. G-guided generative multilevel networks for sparsely sampled MR-PET input are shown here. Compressed Sensing using conjugate symmetry and Partial Fourier methodology speeds up data collection over k-space sampling methods. GANs and k-space adjustments are used in this image domain technique. The employed methodology utilizes discrete preprocessing stages to effectively tackle the challenges associated with the deblurring, reducing motion artifacts, and denoising of layers. Initial trials offer contextual details and accelerate evaluations. Preliminary experiments provide contextual information and expedite assessments.

Brain PET-MR imaging: how can image quality be improved?

Brain PET-MR imaging: how can image quality be improved?

P15.13.B DEVELOPMENT OF [18F]AG-120 AS AN IMAGING AGENT FOR THE DETECTION OF THE MUTANT ISOCITRATE DEHYDROGENASE 1 IN GLIOMA BY PET

Abstract BACKGROUND Gliomas are highly invasive and infiltrative solid tumors that present significant clinical challenges in terms of achieving complete surgical resection. These tumors often harbor mutated isocitrate dehydrogenase enzymes (mIDH), making them attractive theranostic targets. Therefore, accurately assessing mIDH status is essential for effective patient management. Currently, the presence of mIDH1 is determined either by invasive biopsy or indirectly by measuring the mIDH-derived oncometabolite 2-hydroxyglutarate (2-HG) using magnetic resonance spectroscopy (MRS). The availability of mIDH-targeted radioligands would allow for PET neuroimaging to detect the mIDH1 protein directly and non-invasively. MATERIAL AND METHODS The study involved obtaining 18F-labeled AG-120 (Ivosidenib), an FDA-approved small molecule inhibitor of mIDH, by Cu-mediated radiofluorination of a corresponding diastereomerically pure stannyl precursor. The researchers studied the internalization of [18F]AG-120 in vitro in U251 human glioblastoma cells stably transfected with IDH1 or IDH1R132H. Brain uptake and metabolism of [18F]AG-120 were investigated in healthy CD-1 mice by dynamic PET-MR imaging and radio-chromatographic analyses of plasma and brain tissue. Dynamic PET-CT imaging studies were performed in nude rats bearing U251-IDH1 or U251-IDH1R132H glioblastoma. RESULTS The (S,S)-enantiomer of [18F]AG-120 was successfully prepared, and the procedure was implemented into a remotely-controlled radiosynthesis module. A considerably higher uptake of activity was observed in U251-IDH1R132H cells compared to U251-IDH1 cells (0.422 vs. 0.014% applied activity/μg protein after 120 min incubation). The percentage of non-metabolized [18F]AG-120 in the mouse 30 min post i.v. injection was 85% in plasma and 91% in the brain, respectively. Dynamic PET studies showed limited blood-brain barrier permeation of [18F]AG-120 (SUV &amp;lt; 0.1 within the first 5 min post i.v. injection), which could be significantly increased by inhibiting the p-glycoprotein 1 with cyclosporine A. PET studies with glioblastoma rats indicated slightly higher tumor-to-blood ratios in IDH1R132H-tumors compared to IDH1-tumors (~1.7 vs. ~1.3 at 40-60 min p.i.). CONCLUSION For the first time, pure (S,S)-[18F]AG-120 has been synthesized. In addition, GMP-compliant production is facilitated by the established automated radiosynthesis. Despite limited BBB permeation, [18F]AG-120 shows target-specific internalization in vitro and high metabolic stability in vivo. Furthermore, the slightly higher accumulation of [18F]AG-120 in IDH1R132H-glioblastoma compared to IDH1-glioblastoma in vivo encourages further evaluation of mIDH inhibitors for the noninvasive detection of IDH1R132H in glioma by PET. SUPPORT European-Regional-Development-Fund ERDF and Sächsische-Aufbaubank SAB (#100364142).

Initial Experience of 18 F-FET PET-MR Image Fusion for Evaluation of Recurrent Primary Brain Tumors.

Background An accurate monitoring technique is crucial in brain tumors to choose the best treatment approach after surgery and/or chemoradiation. Radiological assessment of brain tumors is widely based on the magnetic resonance imaging (MRI) modality in this regard; however, MRI criteria are unable to precisely differentiate tumoral tissue from treatment-related changes. This study was conducted to evaluate whether fused MRI and O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) positron emission tomography (PET) can improve the diagnostic accuracy of the practitioners to discriminate treatment-related changes from true recurrence of brain tumor. Methods We retrospectively analyzed 18 F-FET PET/computed tomography (CT) of 11 patients with histopathologically proven brain tumors that were suspicious for recurrence changes after 3 to 4 months of surgery. All the patients underwent MRI and 18 F-FET PET/CT. As a third assessment, fused 18 F-FET PET/MRI was also acquired. Finally, the diagnostic accuracy of the applied modalities was compared. Results Eleven patients aged 27 to 73 years with a mean age of 47 ± 13 years were enrolled. According to the results, 9/11 cases (82%) showed positive MRI and 6 cases (55%) showed positive PET/CT and PET/MRI. Tumoral recurrence was observed in six patients (55%) in the follow-up period. Based on the follow-up results, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64, 85, 25, 67, and 50%, respectively, for MRI alone and 91, 85, 100, 100, and 80%, respectively, for both PET/CT and PET/MRI. Conclusion This study found that 18 F-FET PET-MR image fusion in the management of brain tumors might improve recurrence detection; however, further well-designed studies are needed to verify these preliminary data.

Multiplex core of the human brain using structural, functional and metabolic connectivity derived from hybrid PET-MR imaging.

With the increasing success of mapping brain networks and availability of multiple MR- and PET-based connectivity measures, the need for novel methodologies to unravel the structure and function of the brain at multiple spatial and temporal scales is emerging. Therefore, in this work, we used hybrid PET-MR data of healthy volunteers (n = 67) to identify multiplex core nodes in the human brain. First, monoplex networks of structural, functional and metabolic connectivity were constructed, and consequently combined into a multiplex SC-FC-MC network by linking the same nodes categorically across layers. Taking into account the multiplex nature using a tensorial approach, we identified a set of core nodes in this multiplex network based on a combination of eigentensor centrality and overlapping degree. We introduced a coreness coefficient, which mitigates the effect of modeling parameters to obtain robust results. The proposed methodology was applied onto young and elderly healthy volunteers, where differences observed in the monoplex networks persisted in the multiplex as well. The multiplex core showed a decreased contribution to the default mode and salience network, while an increased contribution to the dorsal attention and somatosensory network was observed in the elderly population. Moreover, a clear distinction in eigentensor centrality was found between young and elderly healthy volunteers.

Development of an economical method to synthesize O-(2-[18 F]fluoroethyl)-L-tyrosine (18 FFET).

Positron emission tomography (PET) using O-(2-[18 F]fluoroethyl)-L-tyrosine ([18 F]FET) has shown great success in differentiating tumor recurrence from necrosis. In this study, we are reporting the experience of synthesis [18 F]FET by varying the concentration of TET precursor in different chemistry modules. TET precursor (2-10mg) was used for the synthesis of [18 F]FET in an automated (MX Tracerlab) module (n = 6) and semiautomated (FX2N Tracerlab) module (n = 19). The quality control was performed for all the preparations. For human imaging, 220 ± 50 MBq of [18 F]FET was briefly injected into the patient to acquire PET-MR images. The radiochemical purity was greater than 95% for the final product in both modules. The decay corrected average yield was 10.7 ± 4.7% (10mg, n = 3) and 8.2 ± 2.6% (2mg, n = 3) with automated chemistry module and 36.7 ± 7.3% (8-10mg, n = 12), 26.4 ± 3.1% (5-7mg, n = 4), and 35.1 ± 3.8% (2-4mg, n = 3) with semiautomated chemistry modules. The PET imaging showed uptake at the lesion site (SUVmax = 7.5 ± 2.6) and concordance with the MR image. The [18 F]FET was produced with a higher radiochemical yield with 2.0mg of the precursor with substantial yield and is suitable for brain tumor imaging.

18F-MFBG PET imaging in patients with neuroblastoma: Lesion targeting and comparison with MIBG.

10046 Background: 123I-MIBG gamma camera imaging (MIBG) is routinely used for the imaging of neuroblastoma. Limitations include need for two-day imaging schedule and lack of quantitative uptake measurements. Phase I study showed that 18 F-MFBG (MFBG), a positron-emitting analog of MIBG, is safe and feasible (PMID:28705916). In the follow-up phase II trial (NCT02348749) we evaluated MFBG PET imaging, comparing neuroblastoma lesion between the two modalities. Methods: Patients with known neuroblastoma underwent whole- body PET CT or PET-MR imaging one hour post-injection with 8mCi/1.7m2 of MFBG. All patients had concurrent MIBG scan with planar and SPECT-CT imaging without intervening therapy. MFBG and MIBG images were independently analyzed for lesion targeting; lesion number, site and uptake was noted for each patient and compared. Discordant lesions were further investigated with correlative imaging and/or clinical follow up. MFBG score was generated, similar to the modified Curie score for MIBG, for each patient. Results: 25 patients (median age 8 y) underwent MFBG scans at a median of 2 (range 0-24) days after MIBG scans; in one patient MFBG scan was performed 1 day before MIBG scan. No MFBG-related adverse events were noted. 24 patients had both MIBG and MFBG positive scans while 1 patient had both MIBG and MFBG negative scans. A total of 367 lesions were visualized on MFBG as against 217 on MIBG. There were no MIBG-positive that were negative on MFBG. A median number of 11 (range 0-57) lesions per patient were detected on MFBG scan. Uptake was noted in osteomedullary only, (n=13), soft tissue only (n=1) and both soft tissue and osseous lesions (n=10). MFBG detected a median of 6 (range 1-24) additional lesions in 19 patients. In 16/19 patients where follow up was available, the discordance was related to true positive disease, including at least 116 sites. Respective median curie scores were 3 (range:0-22) and 9 (range:0-24) with MIBG and MFBG respectively. Conclusions: MFBG scan detected disease in all patients with MIBG positive disease. MFBG detected similar or more lesions compared to MIBG in patients with neuroblastoma, with overall increased scores. Further analysis to evaluate impact on patient management is underway. Clinical trial information: NCT02348749 .

PO-02-216 SEGMENTAL INCREASE IN HETEROGENEITY OF REPOLARIZATION CORRESPONDS TO REGIONS OF DECREASED INNERVATION AFTER MYOCARDIAL INFARCTION

Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous remodeled border zone. In this region denervation and nerve regeneration during healing could be region dependent and contribute to segmental differences in the functional substrate for arrhythmias. To examine regional electrophysiological remodeling in relation to perfusion and innervation changes after myocardial infarction. Anterio-septal MI was induced in 6 domestic pigs by a 120-minute occlusion of the left anterior descending artery (LAD) followed by reperfusion. After one month, PET-MR imaging was performed to evaluate myocardial perfusion (13N-ammonia) and innervation (11C-epinephrine), together with late gadolinium enhanced MR imaging for scar quantification. The next day electro-anatomical mapping was performed. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and 1.5 mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the beat-to-beat variability of repolarization (BVR). Spatial heterogeneity of repolarization was quantified in each point as the repolarization time variability within a 1cm radius neighborhood. MI size was 14.2±3.2% of the left ventricle on gadolinium enhanced MR imaging. The perfusion and innervation defects were significantly larger (22.3±3.2%, P<0.01 and 28.1±4.3%, P<0.01 respectively). The innervation defect was also significantly larger than the perfusion defect (P=0.03). Regional analysis revealed less innervation in the anterior versus the septal border zone (14.2±2.9 %/min vs 18.6+3.1 %/min, P<0.01). In one animal the electrophysiology study was unsuccessful due to a high baseline heart rate (>120 BPM). In the remaining animals, the average spatial heterogeneity was higher in the anterior than septal border zone (5.8±3.0 ms vs 3.8±2.6 ms, P<0.01). Additionally, the maximum BVR tended to be higher in the anterior than septal border zone (2.6±1.3 ms vs 2.02±0.77 ms, P=0.08). MI resulting from LAD occlusion/reperfusion leads to increased denervation on the anterior side of the infarct, correlating with increased repolarization heterogeneity in this region.

Quantitative assessment of translocator protein (TSPO) in the non-human primate brain and clinical translation of [18F]LW223 as a TSPO-targeted PET radioligand

ObjectivesTranslocator protein 18 kDa (TSPO) positron emission tomography (PET) can be harnessed for the non-invasive detection of macrophage-driven inflammation. [18F]LW223, a newly reported TSPO PET tracer which was insensitive to rs6971 polymorphism, showed favorable performance characteristics in a recent imaging study involving a rat myocardial infarction model. To enable quantitative neuroimaging with [18F]LW223, we conducted kinetic analysis in the non-human primate (NHP) brain. Further, we sought to assess the utility of [18F]LW223-based TSPO imaging in a first-in-human study. MethodsRadiosynthesis of [18F]LW223 was accomplished on an automated module, whereas molar activities, stability in formulation, lipophilicity and unbound free fraction (fu) of the probe were measured. Brain penetration and target specificity of [18F]LW223 in NHPs were corroborated by PET-MR imaging under baseline and pre-blocking conditions using the validated TSPO inhibitor, (R)-PK11195, at doses ranging from 5 to 10 mg/kg. Kinetic modeling was performed using one-tissue compartment model (1TCM), two-tissue compartment model (2TCM) and Logan graphical analyses, using dynamic PET data acquisition, arterial blood collection and metabolic stability testing. Clinical PET scans were performed in two healthy volunteers (HVs). Regional brain standard uptake value ratio (SUVr) was assessed for different time intervals. Results[18F]LW223 was synthesized in non-decay corrected radiochemical yields (n.d.c. RCYs) of 33.3 ± 6.5% with molar activities ranging from 1.8 ± 0.7 Ci/µmol (n = 11). [18F]LW223 was stable in formulation for up to 4 h and LogD7.4 of 2.31 ± 0.13 (n = 6) and fu of 5.80 ± 1.42% (n = 6) were determined. [18F]LW223 exhibited good brain penetration in NHPs, with a peak SUV value of ca. 1.79 in the whole brain. Pre-treatment with (R)-PK11195 substantially accelerated the washout and attenuated the area under the time-activity curve, indicating in vivo specificity of [18F]LW223 towards TSPO. Kinetic modeling demonstrated that 2TCM was the most suitable model for [18F]LW223-based neuroimaging. Global transfer rate constants (K1) and total volumes of distribution (VT) were found to be 0.10 ± 0.01 mL/cm3/min and 2.30 ± 0.17 mL/cm3, respectively. Dynamic PET data analyses across distinct time windows revealed that the VT values were relatively stable after 60 min post-injection. In a preliminary clinical study with two healthy volunteers, [18F]LW223 exhibited good brain uptake and considerable tracer retention across all analyzed brain regions. Of note, an excellent correlation between SUVr with VT was obtained when assessing the time interval from 20 to 40 min post tracer injection (SUVr(20–40 min), R2 = 0.94, p < 0.0001), suggesting this time window may be suitable to estimate specific binding to TSPO in human brain. ConclusionOur findings indicate that [18F]LW223 is suitable for quantitative TSPO-targeted PET imaging in higher species. Employing state-of-the-art kinetic modeling, we found that [18F]LW223 was effective in mapping TSPO throughout the NHP brain, with best model fits obtained from 2TCM and Logan graphical analyses. Overall, our results indicate that [18F]LW223 exhibits favorable tracer performance characteristics in higher species, and this novel imaging tool may hold promise to provide effective neuroinflammation imaging in patients with neurological disease.