Radiotracer Injection Research Articles

The Effect of Monitored Walking on Extracardiac Intestinal Activity in Myocardial Perfusion Imaging.

Various techniques have been used in attempts to reduce interfering gastrointestinal activity in myocardial perfusion imaging (MPI); however, these approaches have yielded inconsistent results. The goal of this study was to investigate the efficacy of monitored walking, a previously unexplored technique, in reducing subdiaphragmatic activity-related artifacts during pharmacologic stress 99mTc-tetrofosmin MPI with SPECT to improve the overall image quality. Methods: The study included patients who underwent MPI with pharmacologic stress. They were given a step counter immediately after the radiotracer injection and were randomized into a group A, with a request to walk at least 1,000 steps before imaging, and a group B, with no specific instructions about walking. The reconstructed SPECT images were assessed visually. Moderate and severe levels of subdiaphragmatic tracer activity were considered relevant for the interpretation of the scans. Additionally, myocardial and abdominal activity was semiquantitatively assessed on raw planar images, and the mean myocardium-to-abdomen count ratios were calculated. Results: We enrolled 199 patients (95 patients in group A and 104 patients in group B). Clinical characteristics did not differ significantly between the 2 groups. Patients in group A walked more steps than patients in group B (P < 0.001), but there were no differences in the proportion of accepted scans between the 2 groups (P = 0.41). Additionally, there were no differences in the proportion of relevant subdiaphragmatic activity between the groups (P = 0.91). The number of steps did not impact the acceptance rate (P = 0.29). Conclusion: A higher number of steps walked during the waiting period between pharmacologic stress and acquisition does not affect subdiaphragmatic activity-related artifacts or the proportion of accepted scans after pharmacologic stress. However, pedometer use and clear instructions motivate patients to walk while awaiting imaging. Larger studies are required to compare a higher-step-count group with a sedentary control group to assess the influence of walking on gastrointestinal artifacts in MPI.

Ex-SPECTing success: Predictors of successful SPECT radiotracer injection during presurgical video-EEG admissions.

To determine predictors of successful ictal single photon emission computed tomography (SPECT) injections during Epilepsy Monitoring Unit (EMU) admissions for patients undergoing presurgical evaluation for drug-resistant focal epilepsy. In this retrospective study, consecutive EMU admissions were analyzed at a single center between 2019 and 2021. All seizures that occurred during the admission were reviewed. "Injectable seizures" occurred during hours when the radiotracer was available. EMU-level data were analyzed to identify factors predictive of an EMU admission with a successful SPECT injection (successful admission). Seizure-level data were analyzed to identify factors predictive of an injectable seizure receiving a SPECT injection during the ictal phase (successful injection). A multivariate generalized linear model was used to identify predictive variables. 125 EMU admissions involving 103 patients (median 37 years, IQR 27.0-45.5) were analyzed. 38.8% of seizures that were eligible for SPECT (n = 134) were successfully injected; this represented 17.4% of all seizures (n = 298) that occurred during admission. Unsuccessful admissions were most commonly due to a lack of seizures during EMU-SPECT (19.3%) or no injectable seizures (62.3%). Successful EMU-SPECT was associated with baseline seizure frequency >1 per week (95% CI 2.1-3.0, P < 0.001) and focal PET hypometabolism (95% CI 2.0-3.7, P < 0.001). On multivariate analysis, the only factor associated with successful injection was patients being able to indicate they were having a seizure to staff (95% CI 1.0-4.4, P = 0.038). Completing a successful ictal SPECT study remains challenging. A baseline seizure frequency of >1 per week, a PET hypometabolic focus, and a patient's ability to indicate seizure onset were identified as predictors of success. These findings may assist EMUs in optimizing their SPECT protocols, patient selection, and resource allocation.

Abstract Mo036: DNA Damage and Repair in Patients Undergoing Myocardial Perfusion Single-Photon Emission Computed Tomography

Background: As medical imaging has continuously grown, patient exposure to ionizing radiation and the risks associated with it are important issues. Myocardial perfusion single-photon emission computed tomography (MP-SPECT) is one of the most frequently performed noninvasive cardiac imaging tests, generating concern about the potentially excessive radiation exposure for patients, including the cumulative doses of lifetime radiation. even though the individual levels of radiation exposure are considered low. Aim: To evaluate DNA damage and DNA repair markers after MP-SPECT. Methods: Thirty-two patients undergoing Tc-99m sestamibi MP-SPECT (mean injected Tc-99m sestamibi dose: 15.1 mCi) were studied. Peripheral blood was collected before radiotracer injection at rest and 60-90 minutes after injection. The comet assay (single-cell gel electrophoresis) was performed with blood lymphocytes to detect DNA strand breaks, which appear as DNA fragmentation (the comet tail; Figure1). Images of fluorescence microscopy were analyzed using the Comet Assay Software Project Lab (CASPLab 1.2.3 beta 2). Three parameters were evaluated: the percentage of DNA in the comet tail, tail length, and tail moment (the measure of migratory DNA and number of fragments). Quantitative PCR (qPCR) was performed to evaluate the expression of five genes related to signaling pathways in response to DNA damage and repair (ATM, ATR, BRCA1, CDKN1A, XPC). Data are expressed as medians, and Wilcoxon or Mann-Whitney tests were employed for statistical analysis. A p-value &lt;0.05 was considered statistically significant. Results: Figure 2 shows pre- and post- radiation exposure comet assay parameters. After radiotracer injection, there was a 10.7% increase of the DNA percentage in the tail (pre-exposure median 2.185 vs post-exposure median 2.418, p&lt;0.0065). Tail length increased 6.7% (15.0 pre-exposure vs 16.0 post-exposure, p&lt;0.0034). Tail moment increased 27.5% (0.3177 pre-exposure vs 0.4050 post-exposure, p&lt;0.0001). qPCR did not reveal increased expression of any gene after radiation exposure. Conclusion: An increase in DNA damage was detected after a single radiotracer injection for MP-SPECT, yet unaccompanied by activation of repair genes. This may suggest that DNA damage is not large enough to trigger intense repair responses and might not result in biologically significant DNA damage.

DNA damage and repair in patients undergoing myocardial perfusion single-photon emission computed tomography

As patient exposure to ionizing radiation from medical imaging and its risks are continuing issues, this study aimed to evaluate DNA damage and repair markers after myocardial perfusion single-photon emission computed tomography (MPS). Thirty-two patients undergoing Tc-99m sestamibi MPS were studied. Peripheral blood was collected before radiotracer injection at rest and 60–90 min after injection. The comet assay (single-cell gel electrophoresis) was performed with peripheral blood cells to detect DNA strand breaks. Three descriptors were evaluated: the percentage of DNA in the comet tail, tail length, and tail moment (the product of DNA tail percentage and tail length). Quantitative PCR (qPCR) was performed to evaluate the expression of five genes related to signaling pathways in response to DNA damage and repair (ATM, ATR, BRCA1, CDKN1A, and XPC). Mann–Whitney’s test was employed for statistical analysis; p < 0.05 was considered significant. Mean Tc-99m sestamibi dose was 15.1 mCi. After radiotracer injection, comparing post-exposure to pre-exposure samples of each of the 32 patients, no statistically significant differences of the DNA percentage in the tail, tail length or tail moment were found. qPCR revealed increased expression of BRCA1 and XPC, without any significant difference regarding the other genes. No significant increase in DNA strand breaks was detected after a single radiotracer injection for MPS. There was activation of only two repair genes, which may indicate that, in the current patient sample, the effects of ionizing radiation on the DNA were not large enough to trigger intense repair responses, suggesting the absence of significant DNA damage.

Intra-operative lymphatic mapping and sentinel node biopsy in laryngeal carcinoma using radiotracer injection.

The purpose of this study was to determine the value of sentinel lymph node biopsy (SLNB) in the laryngeal SCC, using intra-operative peri-tumoral injection of Tc-99m-phytate. Patients with biopsy-proven squamous cell carcinoma of the larynx were included. On the day of surgery, after anesthesia induction, suspension laryngoscopy was performed to inject 74MBq/0.4ml Tc-99m-phytate in four aliquots into the sub-mucosal peri-tumoral location. After a 10-min wait, a portable gamma probe was used to locate sentinel nodes. Subsequently, all patients underwent laryngectomy and neck dissection. Both sentinel nodes and non-sentinel nodes were examined using hematoxylin and eosin (H&E) staining. Twenty-six patients with a diagnosis of laryngeal carcinoma were included in the study. The SLN detection rate was 65.4%, with a 100% detection rate in the supraglottic region and a 52.6% detection rate for glottis/transglottic patients. Permanent pathology results showed lymph node involvement in four patients, but only one patient had a negative result in the SLNB, resulting in an overall false negative rate of 25%. The sensitivity of the SLN technique was 75% overall, 100% in the supraglottic region, and 67% in the glottis/transglottic region. The accuracy and feasibility of SLNB may be related to the location of the tumors in the larynx. For supraglottic tumors, the technique seems to be feasible with a low false negative rate. For glottis/transglottic tumors, both the detection rate and false negative rate seem to be suboptimal. Further studies are needed to validate our results.

Accuracy of sentinel node mapping in Marjolin ulcer: Comparison of three different injection techniques

BackgroundMarjolin ulcer is a specific type of squamous cell cancer that can benefit from the use of lymphoscintigraphy.The purpose of this study was to evaluate 3 different injection techniques for sentinel node biopsy in patients with Marjolin ulcer. MethodsForty-eight patients with Marjolin ulcer (27 male and 21 female) ranging in age from 24 to 85 years were included in our study. Intratumoral (IT), peritumoral (PT) and periscar (PS) tissue injections of radiotracer were done in 9, 10, and 29 patients respectively. Injections were done 2–4 h before surgery. Lymphoscintigraphy was done for mapping the lymphatic drainage. During surgery, lymphatic mapping and sentinel node biopsy was performed using a handheld gamma probe. After harvesting sentinel nodes, regional lymph node dissection was done. ResultSentinel node detection rate was higher in the PS group as compared to the IT and PT groups (89.6% vs. 50% and 22.2%) respectively. False negative rate was 0%. Pathologically involved sentinel nodes were detected in 16% of the included patients of our study which led to management change. None of the patients with pathologically non-involved sentinel nodes developed regional lymph node recurrence. ConclusionLymphatic mapping and sentinel node biopsy is feasible in Marjolin ulcer with high detection rate and low false negative cases which by detection of regional lymph node involvement can potentially change the management of patients. Injection site may be an important factor influencing the success of the procedure and injection of the mapping material in the peri-scar normal skin proximal to the lesion is the best technique.

Dynamic whole-body [18F]FES PET/CT increases lesion visibility in patients with metastatic breast cancer

BackgroundCorrect classification of estrogen receptor (ER) status is essential for prognosis and treatment planning in patients with breast cancer (BC). Therefore, it is recommended to sample tumor tissue from an accessible metastasis. However, ER expression can show intra- and intertumoral heterogeneity. 16α-[18F]fluoroestradiol ([18F]FES) Positron Emission Tomography/Computed Tomography (PET/CT) allows noninvasive whole-body (WB) identification of ER distribution and is usually performed as a single static image 60 min after radiotracer injection. Using dynamic whole-body (D-WB) PET imaging, we examine [18F]FES kinetics and explore whether Patlak parametric images (Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document}) are quantitative and improve lesion visibility.ResultsThis prospective study included eight patients with metastatic ER-positive BC scanned using a D-WB PET acquisition protocol. The kinetics of [18F]FES were best characterized by the irreversible two-tissue compartment model in tumor lesions and in the majority of organ tissues. Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} values from Patlak parametric images correlated with Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} values from the full kinetic analysis, r2 = 0.77, and with the semiquantitative mean standardized uptake value (SUVmean), r2 = 0.91. Furthermore, parametric Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} images had the highest target-to-background ratio (TBR) in 162/164 metastatic lesions and the highest contrast-to-noise ratio (CNR) in 99/164 lesions compared to conventional SUV images. TBR was 2.45 (95% confidence interval (CI): 2.25–2.68) and CNR 1.17 (95% CI: 1.08–1.26) times higher in Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} images compared to SUV images. These quantitative differences were seen as reduced background activity in the Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} images.Conclusion[18F]FES uptake is best described by an irreversible two-tissue compartment model. D-WB [18F]FES PET/CT scans can be used for direct reconstruction of parametric Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} images, with superior lesion visibility and Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} values comparable to Ki\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${K}_{i}$$\\end{document} values found from full kinetic analyses. This may aid correct ER classification and treatment decisions.Trial registration ClinicalTrials.gov: NCT04150731, https://clinicaltrials.gov/study/NCT04150731

Sentinel Node Mapping in Ovarian Tumors: A Study Using Lymphoscintigraphy and SPECT/CT.

Ovarian cancer in the early stage requires a complete surgical staging, including radical lymphadenectomy, implying subsequent risk of morbidity and complications. Sentinel lymph node (SLN) mapping is a procedure that attempts to reduce radical lymphadenectomy-related complications and morbidities. Our study evaluates the feasibility of SLN mapping in patients with ovarian tumors by the use of intraoperative Technetium-99m-Phytate (Tc-99m-Phytate) and postoperative lymphoscintigraphy using tomographic (single-photon emission computed tomography/computed tomography (SPECT/CT)) acquisition. Thirty-two patients with ovarian mass participated in this study. Intraoperative injection of the radiopharmaceutical was performed just after laparotomy and before the removal of tumor in utero-ovarian and suspensory ligaments of the ovary just beneath the peritoneum. Subsequently, pelvic and para-aortic lymphadenectomy was performed for malignant masses, and the presence of tumor in the lymph nodes was assessed through histopathological examination. Conversely, lymphadenectomy was not performed in patients with benign lesions or borderline ovarian tumors. Lymphoscintigraphy was performed within 24 hr using tomographic acquisition (SPECT/CT) of the abdomen and pelvis. Final pathological examination showed 19 patients with benign pathology, 5 with borderline tumors, and 6 with malignant ovarian tumors. SPECT/CT identified SLNs in para-aortic-only areas in 6 (20%), pelvic/para-aortic areas in 14 (47%), and pelvic-only areas in 7 (23%) cases. Notably, additional unusual SLN locations were revealed in perirenal, intergluteal, and posterior to psoas muscle regions in three patients. We were not able to calculate the false negative rate due to the absence of patients with involved lymph nodes. SLN mapping using intraoperative injection of radiotracers is safe and feasible. Larger studies with more malignant cases are needed to better evaluate the sensitivity of this method for lymphatic staging of ovarian malignancies.

Evaluation of the diagnostic value of Sentinel Lymph Node in patients with gastric adenocarcinoma.

Sentinel lymph node biopsy (SLNB) has been proven as a safe and efficient procedure in some cancers like breast cancer and melanoma with a reduction of complications and side effects of unnecessary lymphadenectomy in many patients. However, the diagnostic value of SLNB in gastric cancer is a point of debate. This study evaluated the diagnostic value of SLNB using radiotracer and isosulphan blue dye injection in patients with Gastric Adenocarcinomas (GA). This descriptive study was performed at Imam-Reza HOSPITAL on 39 patients diagnosed with GA with no lymphatic metastasis using two methods: the combination of radionuclide with isosulphan together (R&I) method compared with the isosulphan alone method. Lymphatic dissection was performed in all patients. The pathological results were compared between the sentinel lymph nodes (SLN) and other lymph nodes and their accordance rate was calculated. In the T1 group, the sentinel lymph node biopsy detection rate was 100% for the combination of the R&I method and 60% for the isosulphan method and the false negative rate was zero. These values respectively were 88.8% and 88.8% in the T2 group with a false negative rate of 75%. In the T3 group, the values were 100% for the combination of the R&I method and 93.7% for the isosulphan method with a false negative rate of 40%. In the combination of the R&I method, the sensitivity, specificity, and positive and negative predictive values were 57.9, 100, 100, and 69.2 percent respectively. Based on the false negative rate (47.4%), SLNB by injection of isosulphan blue dye alone is not a diagnostic enough value for predicting lymph node metastasis in GA. Although, SLNB by combination of the R&I had better accuracy compared to the isosulphan alone, more studies with larger samples are needed to prove this result.

Assessing amyloid plaque burden in aging marmosets and genetically engineered PSEN1 mutation carriers using 11C‐PiB PET

AbstractBackgroundThere is an urgent need to develop novel animal models to investigate the underlying cellular and molecular root causes of the pathogenesis and progression of AD. Our group has worked to establish the common marmoset as the first primate‐specific model of AD to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception. For this, we established a colony of outbred marmosets and used genetic engineering techniques to generate marmosets carrying the PSEN1‐C410Y and PSEN1‐A426P mutations that cause early‐onset, familial AD. The present study aims to use PET imaging to access and track the progression of Ab plaque burden non‐invasively and longitudinally in our marmoset models of AD.MethodMarmosets anesthetized with isoflurane delivered via a facemask were placed in a preclinical PET/CT scanner customized with marmoset‐specific beds. Respiratory rate, heart rate, arterial O2 saturation, and rectal temperature were monitored and maintained at normal physiological values. Our PET imaging protocol follows the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The amyloid‐binding 11C‐Pittsburgh Compound B (11C‐PiB) was delivered intravenously in doses varying from 18.5 – 185 MBq (0.5 – 5 mCi). A 90‐min dynamic acquisition was performed immediately following the radiotracer injection, followed by a 3D CT scan acquired at 200 µm isotropic resolution. After the PET/CT neuroimaging scan, the marmosets were recovered from anesthesia and returned to their home cages.ResultWe observed positive 11C‐PiB binding and retention in the brains of aging outbred marmosets and in marmosets harboring PSEN1 mutations. Significant 11C‐PiB retention was observed in the cortex and white matter tracts. The areas with the highest 11C‐PiB retention were the lateral frontal cortex, anterior cingulate cortex, and temporal lobe regions.ConclusionThis study demonstrates using 11C‐PiB to track Ab plaque burden in the brains of aging marmosets and marmosets harboring PSEN1 mutations. As observed in human patients of AD, the amount of 11C‐PiB bound (measured in SUV and SUVR units) varied from animal to animal, and we are currently performing group analysis to investigate the dependence of 11C‐PiB retention on age and sex. This research was funded by NIH/NIA grants R24AG073190 and U19AG074866.

Assessing amyloid plaque burden in aging marmosets and genetically engineered PSEN1 mutation carriers using 11C‐PiB PET

AbstractBackgroundThere is an urgent need to develop novel animal models to investigate the underlying cellular and molecular root causes of the pathogenesis and progression of AD. Our group has worked to establish the common marmoset as the first primate‐specific model of AD to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception. For this, we established a colony of outbred marmosets and used genetic engineering techniques to generate marmosets carrying the PSEN1‐C410Y and PSEN1‐A426P mutations that cause early‐onset, familial AD. The present study aims to use PET imaging to access and track the progression of Ab plaque burden non‐invasively and longitudinally in our marmoset models of AD.MethodMarmosets anesthetized with isoflurane delivered via a facemask were placed in a preclinical PET/CT scanner customized with marmoset‐specific beds. Respiratory rate, heart rate, arterial O2 saturation, and rectal temperature were monitored and maintained at normal physiological values. Our PET imaging protocol follows the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The amyloid‐binding 11C‐Pittsburgh Compound B (11C‐PiB) was delivered intravenously in doses varying from 18.5 – 185 MBq (0.5 – 5 mCi). A 90‐min dynamic acquisition was performed immediately following the radiotracer injection, followed by a 3D CT scan acquired at 200 µm isotropic resolution. After the PET/CT neuroimaging scan, the marmosets were recovered from anesthesia and returned to their home cages.ResultWe observed positive 11C‐PiB binding and retention in the brains of aging outbred marmosets and in marmosets harboring PSEN1 mutations. Significant 11C‐PiB retention was observed in the cortex and white matter tracts. The areas with the highest 11C‐PiB retention were the lateral frontal cortex, anterior cingulate cortex, and temporal lobe regions.ConclusionThis study demonstrates using 11C‐PiB to track Ab plaque burden in the brains of aging marmosets and marmosets harboring PSEN1 mutations. As observed in human patients of AD, the amount of 11C‐PiB bound (measured in SUV and SUVR units) varied from animal to animal, and we are currently performing group analysis to investigate the dependence of 11C‐PiB retention on age and sex.This research was funded by NIH/NIA grants R24AG073190 and U19AG074866.

PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84.

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.

Abstract A149: Characterization of HER3 targeted radioligand therapy using molecular imaging

Abstract Background: Radioligand therapy (RLT) is an emerging treatment modality that has shown potential to improve survival in cancer patients that often have limited or non-effective therapeutic options. We previously demonstrated that anti-HER3 antibody radioconjugate (HER3 ARC) has antitumor efficacy against HER3 expressing tumor xenograft models. One important step in the early development of RLT is to understand the targeting properties and the distribution of the RLT in vivo. Non-invasive molecular imaging such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer unique opportunities to understand drug behavior in vivo, permitting real time drug targeting and distribution analysis. In this study, we assessed the targeting properties and distribution of our HER3 ARC in HER3 expressing preclinical xenograft tumor models using both SPECT and PET. Methods: HER3 monoclonal antibody was conjugated with p-SCN-Bn-deferoxamine (DFO) or p-SCN-Bn-DOTA (DOTA) then labeled with Zirconium-89 (89Zr) or Indium-111 (111In), respectively. Flow cytometry and gamma counting was used to characterize HER3 ARC biological activity in HER3-expressing tumor cell lines. Balb/c mice subcutaneously inoculated with HER3-expressing xenograft tumors (lung, ovarian and colorectal) were intravenously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3. PET or SPECT scans were acquired 72 and 120-144hrs post injection of the radiotracer. Separate cohorts of mice were simultaneously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3 and 20-fold excess of native HER3 antibody as control to block radiotracer binding. Tissue uptake was quantified by drawing 3D or 2D regions of interest (ROI) for PET or SPECT images, respectively. Results: HER3 ARC radiotracers were successfully prepared and demonstrated similar binding to HER3 expressing cells compared to native HER3 antibody. In tumor-bearing mice, 89Zr-DFO-HER3 and 111In-DOTA-HER3 specifically accumulated in HER3 expressing tumors and cleared throughout the reticuloendothelial system. High tumor uptake was observed 120hrs post radiotracer injection using both imaging modalities. In mice pre-treated with 20-fold excess of native antibody, tumor uptake was significantly lower, showing tumor binding specificity of ARC. PET and SPECT images showed similar tracer distribution profile in the HER3 tumors. As expected, radiotracer clearance organ signals were also visualized. Conclusions: In this study we show that PET or SPECT imaging using 89Zr or 111In, respectively, offers the potential to assess the distribution of HER3 targeted radioligand therapy during early stages of drug development. HER3 ARC showed highly specific HER3 tumor uptake that remained at least 120hrs post injection. Our findings warrant further investigation to support advancement of HER3 ARC as a therapeutic option. Citation Format: Sumit Mukherjee, Debbie Lewis, Jason Li, Le-Cun Xu, Amanda Chin, Mary Chen, Monideepa Roy, Patrik Brodin, William van der Touw, Helen Kotanides, Denis Beckford-Vera. Characterization of HER3 targeted radioligand therapy using molecular imaging [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A149.

Serial 18F-Florbetaben Positron Emission Tomography and Cardiac Magnetic Resonance Imaging in the Evaluation of Systemic Light Chain Cardiac Amyloidosis Enhances Diagnostic and Response Assessment Accuracy

Background: There is a need for improved assessment of cardiac involvement in systemic amyloidosis by non-invasive methods to increase accuracy of diagnosis and to assist with monitoring and prognostication of the condition. We have previously shown that 18F-florbetaben, a novel amyloid binding radiotracer, can identify the presence of cardiac amyloid in positron emission tomography (PET/CT) imaging. We aim to evaluate the role of imaging with 18F-florbetaben PET/CT, cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) in the initial diagnosis and response assessments of patients with light chain (AL) cardiac amyloidosis (AL-CA). Methods: Twelve patients diagnosed with systemic AL amyloidosis and proven or suspected cardiac involvement, between June 2018 and December 2020, were prospectively recruited to undergo 18F-florbetaben PET/CT, CMR and TTE imaging prior to commencement and 6 months post systemic therapy. 40-minute dynamic and static PET/CT images were acquired following 18F-florbetaben radiotracer injection. Left ventricular myocardial standardised uptake values (SUV) were recorded and used to graph time activity curves (TAC). Percentage myocardial tracer retention (MTR) was derived from the dynamic data. CMR was performed using a 3.0T MRI system. The Modified Look-Locker Inversion recovery (MOLLI) method was utilized to generate native and gadolinium-enhanced T1 mappings, which were then used to calculate the global extracellular volume (ECV). PET and CMR indices were compared to 2D-speckled TTE metrics and cardiac biomarkers (BNP, cTnI) using Pearson Correlation for statistical analysis. Overall survival was calculated using the Kaplan-Meir method. Results: Participant characteristics were as per table 1. Five deaths occurred during the study, all due to progressive AL amyloidosis; with 4 of these occurring prior to the planned second imaging timepoint. Two-year survival was 58.3%, with a mean overall survival of 7.3 years (95% CI 4.08 - 10.52). All patients had a baseline PET/CT; 8 were able to have a concurrent CMR. The remaining 4 were unable have a CMR due to incompatible devices or were clinically unwell at the time. Seven patients went on to have a repeat PET/CT and 5 had comparative CMR imaging 6 months after commencing treatment. Baseline 18F-florbetaben PET/CT scans demonstrated characteristic AL-CA patterns of prolonged myocardial tracer retention TAC in 10 out of the 12 patients (Figure 1). Patients' 8 and 12 TACs (highlighted with arrows in Figure 1) did not follow the usual AL-CA MTR pattern and their MTRs were calculated to be below a previously defined threshold of ≥40% for the presence of cardiac amyloid. This prompted review of the diagnosis of AL-CA in these patients and both were found to have alternative causes for the TTE and cardiac biomarker abnormalities which were initially interpreted as AL-CA. Analysis of the different imaging metrics showed significant correlation between MTR and ECV (r=0.575; p=0.04) as well as ECV and GLS (r=0.62; p=0.024). ECV also correlated with BNP (r=0.637; p=0.019) as did GLS and BNP (r=0.678; p=0.002). There was no association between MTR and cardiac biomarkers. 8 patients were assessable at the 6-month timepoint; only 1 patient had a cardiac response at 6 months by the International Society of Amyloidosis (ISA) criteria and they demonstrated a &amp;gt;10% reduction in MTR on follow-up PET/CT. Two patients had stable cardiac disease as per ISA criteria: 1 had &amp;gt;10% reduction in MTR and went on to achieve subsequent cardiac response without further therapy; the other had an increase in MTR by 18.5% and went on to salvage ASCT for suboptimal haematological and cardiac responses (partial remission and stable organ disease). Four patients had cardiac progression by ISA criteria with a worsening of MTR by at least 15% (mean=19.1%). Conclusion: Patients with AL-CA display prolonged 18F-florbetaben retention on PET/CT imaging which also appears useful to exclude the presence of cardiac amyloidosis in patients with co-existent cardiac conditions. Preliminary data supports the role of 18F-florbetaben PET/CT in cardiac response assessment, but further studies are required to determine the optimal timing of follow up imaging, which is likely to be beyond the 6-month time point, and to determine clinically significant MTR ranges for monitoring and prognostication.

Adenosine-induced splenic switch-off on [15O]H2O PET perfusion for the assessment of vascular vasodilatation

BackgroundSplenic switch-off (SSO) is a marker of adequate adenosine-induced vasodilatation on cardiac magnetic resonance perfusion imaging. We evaluate the feasibility of quantitative assessment of SSO in myocardial positron emission tomography (PET) perfusion imaging using [15O]H2O.MethodsThirty patients underwent [15O]H2O PET perfusion with adenosine stress. Time-activity curves, as averaged standardized uptake values (SUVavg), were extracted from dynamic PET for spleen and liver. Maximum SUVavg, stress and rest spleen-to-liver ratio (SLR), and the splenic activity concentration ratio (SAR) were computed. Optimal cut-off values for SSO assessment were estimated from receiver operating characteristics (ROC) curve for maximum SUVavg and SLR. Also, differences between coronary artery disease, myocardial ischemia, beta-blockers, and diabetes were assessed. Data are presented as median [interquartile range].ResultsIn concordance with the SSO phenomenon, both the spleen maximum SUVavg and SLR were lower in adenosine stress when compared to rest perfusion (8.1 [6.5, 9.2] versus 16.4 [13.4, 19.0], p < 0.001) and (0.81 [0.63, 1.08] versus 1.86 [1.73, 2.06], p < 0.001), respectively. During adenosine stress, the SSO effect was most prominent 40–160 s after radiotracer injection. Cut-off values of 12.6 and 1.57 for maximum SUVavg and SLR, respectively, were found based on ROC analysis. No differences in SAR, SLRRest, or SLRStress were observed in patients with coronary artery disease, myocardial ischemia, or diabetes.ConclusionsSSO can be quantified from [15O]H2O PET perfusion and used as a marker for adequate adenosine-induced vasodilatation response. In contrary to other PET perfusion tracers, adenosine-induced SSO is time dependent with [15O]H2O.

Abstract 17405: Biodistribution, Dosimetry, and Specificity of A 99m Tc-Labeled Matrix Metalloproteinase Targeted Radiotracer ( 99m Tc-RP805) for Myocardial Infarct Imaging

Introduction: Activation of matrix metalloproteinase (MMPs) post myocardial infarction (MI) predicts post-MI remodeling. MMP activation in the heart can be detected using 99mTc-RP805 a radiolabel peptidomimetic that binds to the catalytic site. The purpose of this study was to evaluate the biodistribution, dosimetry, and specificity of clinical grade 99mTc-RP805 for first-in-human studies. Methods: Male and female rats (n=24) were injected with 99m Tc-RP805 and euthanized at 1, 3, 7 or 12 hr post injection to determine biodistribution and estimate human dosimetry. Organ activity (%ID/g) was used to estimate whole body and organ effective dose using OLINDA. MI was induced in rats by LAD ligation (n=19) and injected with 99m Tc-RP805 3 days post MI, and rats were euthanized 3 hr after injection in absence (n=9) or presence (n=10) of a 100 x blocking dose of RP805 (257 ug/kg) 30 min prior to radiotracer injection to establish specificity. In vivo SPECT/CT imaging was performed with GMP grade 99m Tc-RP805 in rats post-MI (n=4). Results: The %ID/g for each organ is presented per time point (Fig 1 A). The highest radiation dose was found in male kidneys at 3 hr (%ID/g: 6.11 ± 0.54), female kidneys at 1hr (%ID/g: 6.31 ± 0.88). The estimated total body dose for human males was calculated at 0.172 mSv/mCi and 0.283 mSv/mCi for females, equaling a dose of 3.4 mSv and 5.7 mSv for a 30 mCi injection in males and females, respectively. There is 4 fold increase 99mTc-RP805 uptake in the infarct area compared to the normal LV (Fig 1B) and uptake was blocked with cold compound (ANOVA, p&lt;0.001). In vivo SPECT/CT imaging with a newly synthesized GMP compound demonstrates uptake in the anterior LV (Fig 1C). Conclusions: We have developed and evaluated clinical grade 99m Tc-RP805 for targeted MMP imaging post-MI and demonstrated favorable dosimetry, biodistribution, and specificity for first-in-human imaging.

Pilot study of HER2 targeted 64 Cu-DOTA-tagged PET imaging in gastric cancer patients.

Human epidermal growth factor receptor 2 (HER2) is an important biomarker for targeted gastric cancer (GC) immunotherapy. However, heterogeneous HER2 overexpression in GC, loss of HER2 expression during therapy, and inability to non-invasively identify HER2 overexpressing tumors impede effective targeting therapies. Improved HER2-specific functional imaging can address these challenges. Trastuzumab is a HER2-directed mAb to treat HER2 overexpressing cancers. The 64 Cu-DOTA-trastuzumab radiotracer is used to detect HER2+ metastatic breast cancer. We aimed to develop 64 Cu-DOTA-trastuzumab PET-CT to detect and characterize tumor uptake in HER2+ or - GC patients. We conducted a single-arm phase II pilot study exploring the feasibility of 64 Cu-DOTA-trastuzumab for PET imaging of HER2 overexpressing GC compared to HER2 non-expressing tumors. Eight patients with biopsy-confirmed gastric adenocarcinoma were included. Immunohistochemistry was used to evaluate primary tumor biopsies for HER2 overexpression. Patients were injected with 45 mg of cold trastuzumab followed by 5 mg of 64 Cu-DOTA-trastuzumab. PET-CT scans were performed 24-48 h post radiotracer injection and compared to standard staging CT scans. We observed limited toxicity following 64 Cu-DOTA-trastuzumab injections. While there was uptake of the radiotracer in portions of HER2+ lesions, there was no statistically significant distinction between tumor and background by standardized uptake value analysis. Despite the potential of 64 Cu-DOTA-trastuzumab PET imaging of HER2+ metastatic breast cancer, a 5 mg dose of this radiotracer injected 24-48 h before imaging was insufficient to identify HER2+ GC. These results inform future GC imaging studies to optimize biomarker-targeted therapies based on dosage and timing for more clinically relevant imaging.

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Parametric Imaging of P-Glycoprotein Function at the Blood-Brain Barrier Using kE,brain-maps Generated from [11C]Metoclopramide PET Data in Rats, Nonhuman Primates and Humans.

PET imaging using [11C]metoclopramide revealed the importance of P-glycoprotein (P-gp, ABCB1) in mediating the brain-to-blood efflux of substrates across the blood-brain barrier (BBB). In this work, the elimination rate constant from the brain (kE,brain), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [11C]metoclopramide PET data. kE,brain parameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). kE,brain values (h-1) obtained under baseline conditions were compared with values obtained after complete P-gp inhibition using tariquidar in rats (n = 4) and baboons (n = 4) or after partial inhibition using cyclosporine A in humans (n = 10). In baboons, the sensitivity of kE,brain to measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, kE,brain-maps were generated in each species using PMOD software. The linear part of the log-transformed brain TACs occurred from 10 to 30min after radiotracer injection in rats, from 15 to 60min in baboons, and from 20 to 60min in humans. P-gp inhibition significantly decreased kE,brain values by 39 ± 12% in rats (p < 0.01), by 32 ± 6% in baboons (p < 0.001), and by 37 ± 22% in humans (p < 0.001). In baboons, P-gp inhibition consistently decreased the brain-to-plasma efflux rate constant k2 (36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (VT, 101 ± 12%, p < 0.001). In all studied species, brain kE,brain-maps displayed decreased P-gp-mediated efflux across the BBB. kE,brain of [11C]metoclopramide provides a simple outcome parameter to describe P-gp function in the living brain when arterial input function data are unavailable, although less sensitive than VT. kE,brain-maps represent easy to compute parametric images reflecting the effect of P-gp on [11C]metoclopramide elimination from the brain.

Identifying and troubleshooting the pitfalls of ictal/interictal brain perfusion SPECT studies.

Epilepsy is a prevalent condition, and surgical intervention can benefit patients with refractory seizures. Single photon emission computed tomography (SPECT) using 99mTc-HMPAO or 99mTc-ECD provides assessment of regional cerebral blood flow and is the primary non-invasive approach for imaging brain perfusion in ictal and interictal states. Ictal/interictal SPECT is valuable in localising epileptogenic foci, particularly when MRI and electroencephalography are negative. However, to obtain accurate images reflecting brain perfusion in both states, meticulous preparation of the patient, timely radiotracer injection and close coordination between neurology and nuclear medicine teams are essential. Tracers also have inherent limitations, and patients may present with coexisting brain pathologies for which coregistration of SPECT images with MRI is recommended to improve diagnostic accuracy. Inconclusive SPECT findings may require repeating the exam or considering additional investigations. A comprehensive approach, considering various factors, is crucial for accurate interpretation of SPECT studies in presurgical epilepsy evaluations. This article provides a summary of the organisation and key challenges involved in conducting ictal/interictal SPECT studies, covering the entire process from a patient's hospital arrival to the integration of results within their presurgical pathway and using our experience of 182 patients over 10 years.