Purpose In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). Methods Forty-nine participants were scanned with 18 F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. Results SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18 F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. Conclusion Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18 F-PI-2620 in patients along the AD trajectory. This work confirms that 18 F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

The aim of this study was development of an improved PET radiotracer for measuring x C − activity with increased tumor uptake and reduced uptake in inflammatory cells compared with (S)-4-(3-18 F-fluoropropyl)-L-glutamate ( 18 F-FSPG). Methods: A racemic glutamate derivative, 18 F-hGTS13, was evaluated in cell culture and animal tumor models. 18 F-hGTS13 was separated into C5 epimers, and the corresponding 18 F-hGTS13-isomer1 and 18 F-hGTS13-isomer2 were evaluated in H460 tumor-bearing rats. Preliminary studies investigated the cellular uptake of 18 F-hGTS13-isomer2 in multiple immune cell populations and states. Results: 18 F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for 18 F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g, n 5 3) than for 18 F-FSPG (4.6 ± 0.7 %ID/g, n 5 3, P 5 0.01). 18 F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g, n 5 3) and significantly reduced uptake in multiple immune cell populations relative to 18 F-FSPG. 18 F-hGTS13-isomer2 exhibited increased liver uptake relative to 18 F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. Conclusion: 18 F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of x C − activity that may provide information on tumor oxidation states. 18 F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.

Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO)-positron emission tomography (PET) is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo, however it is yet to be fully explored in PD. Herein we investigate the utility of TSPO-PET, in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1) -a novel biomarker of proinflammatory innate immune cells -for detecting innate immune responses in the 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1-knockout mice were stereotaxically injected with 6-OHDA in the left striatum; control mice were saline-injected. At day 7 or 14 post-surgery, mice were administered 18 F-GE-180, 64 Cu-TREM1-mAb or 64 Cu-Isotype control-mAb and imaged by PET/CT. Ex vivo autoradiography (ARG) was performed to obtain high resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death and quantitative PCR and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-OHDA-injected mice compared to those injected with saline. ARG afforded higher resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-OHDA-compared to salineinjected mice at both 7-and 14-days post-toxin. Interestingly, 18 F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-OHDA mice, whereas 64 Cu-TREM1-mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO-and TREM1-PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.

Introduction: Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by abnormal aggregation of two proteins, tau and amyloid beta. We assessed tau pathology and white matter connectivity changes in subfields of the hippocampus simultaneously in vivo in AD.Methods: Twenty-four subjects were scanned using simultaneous time-of-flight 18 F-PI-2620 tau positron emission tomography/3-Tesla magnetic resonance imaging and automated segmentation. Results:We observed extensive tau elevation in the entorhinal/perirhinal regions, intermediate tau elevation in cornu ammonis 1/subiculum, and an absence of tau elevation in the dentate gyrus, relative to controls. Diffusion tensor imaging showed parahippocampal gyral fractional anisotropy was lower in AD and mild cognitive impairment compared to controls and strongly correlated with early tau accumulation in the entorhinal and perirhinal cortices.Discussion: This study demonstrates the potential for quantifiable patterns of 18 F-PI2620 binding in hippocampus subfields, accompanied by diffusion and volume metrics, to be valuable markers of AD.

Purpose: Determine the safety and specificity of a tumor-targeted radiotracer (89Zr-pan) in combination with 18F-FDG PET/CT to improve diagnostic accuracy in head and neck squamous cell carcinoma (HNSCC). Experimental Design: Adult patients with biopsy-proven HNSCC scheduled for standard of care surgery were enrolled in a clinical trial and underwent systemic administration of 89Zirconium-panitumumab and panitumumab-IRDye800 followed by preoperative 89Zr-pan PET/CT and intraoperative fluorescence imaging. The sensitivity, specificity, and AUC were evaluated. Results: A total of fourteen patients were enrolled and completed the study. Four patients (28.5%) had areas of high 18F-FDG uptake outside the head and neck region with maximum standardized uptake values (SUVmax) greater than 2.0 that were not detected on 89Zr-pan PET/CT. These four patients with incidental findings underwent further workup and had no evidence of cancer on biopsy or clinical follow-up. Forty-eight lesions (primary tumor, LNs, incidental findings) with SUVmax ranging 2.0 – 23.6 were visualized on 18F-FDG PET/CT; 34 lesions on 89Zr-pan PET/CT with SUVmax ranging 0.9 – 10.5. The combined ability of 18F-FDG PET/CT and 89Zr-pan PET/CT to detect HNSCC in the whole body was improved with higher specificity of 96.3% (confidence interval (CI) 89.2 – 100%) compared to 18F-FDG PET/CT alone with specificity of 74.1% (CI 74.1 – 90.6%). One possibly related grade 1 adverse event of prolonged QTc (460 ms) was reported but resolved in follow-up. Conclusions: 89Zr-pan PET/CT imaging is safe and may be valuable in discriminating incidental findings identified on 18F-FDG-PET/CT from true positive lesions and in localizing metastatic LNs.

BackgroundChronic activation of macrophages/microglia plays a critical role in the onset and progression of neurological diseases, including Alzheimer’s. While PET imaging could enable non‐invasive visualization and quantification of activated macrophages/microglia in vivo, most available PET tracers are nonspecific for macrophages/microglia (Lambert, 2009). To address this need, we developed [18F]OP‐801, a synthetic hydroxyl dendrimer‐based PET tracer that is selectively (>95%) taken up by reactive macrophages/microglia across the blood‐brain barrier (Alnasser, 2018). Here, we evaluated the ability of [18F]OP‐801 to detect activated macrophages/microglia in the 5XFAD murine model of Alzheimer’s compared to an established neuroinflammation imaging approach (translocator protein 18 kDa [TSPO]‐PET, using [18F]GE180).Method[18F]OP‐801 (150‐250 μCi) was injected intravenously into female 5XFAD (TG) mice (n=12) and age/sex‐matched wild types (WT, n=7) at 3.75 and 5 months old. Sensitivity of [18F]OP‐801 was compared to [18F]GE180 by assessing brain signal‐to‐background ratios. [18F]GE180 (150‐250 μCi) was administered to a subset of TG (n=5) and WT (n=4) 3.75‐months‐old mice. Static 10‐minute PET/CT images were acquired at 50‐60 minutes post‐injection for both tracers. VivoQuant brain atlas was fit to CT images and fused to PET to quantify uptake in specific brain regions.ResultIn this model, macrophage/microglial activation is associated with amyloid plaque formation and can be detected using immunohistochemistry between 2‐4 months. Image quantification revealed 3‐fold higher PET signal in 3.75‐months‐old TG compared to WT mice using [18F]OP‐801, whereas [18F]GE180 signal provided no significant difference in brain regions known to contain activated microglia: cortex and hippocampus (Figure 1, Table 1). Significant differences in [18F]OP‐801 uptake were observed between 5‐months‐old TG and WT mice in cortex (p=0.005) (TG: 0.26±0.095%ID/g, WT: 0.11±0.041%ID/g), hippocampus (p=0.017) (TG: 0.18±0.065%ID/g, WT: 0.10±0.026%ID/g) and whole brain (p=0.004) (TG: 0.20±0.082%ID/g, WT: 0.10±0.039%ID/g). TG had almost 5‐fold higher [18F]OP‐801 signal compared to WT mice (Table 2).ConclusionThese results suggest that [18F]OP‐801 can detect early stage neuroinflammation with higher sensitivity than TSPO‐PET. We are currently replicating this study in a larger cohort of 5XFAD mice to correlate PET image findings with immunohistochemistry. [18F]OP‐801 is shows promise for visualizing the progression of neuroinflammation with high specificity and sensitivity, warranting further preclinical investigation.

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

Recent events in America in 2020 have stimulated a worldwide movement to dismantle anti-Black racism in all facets of our lives. Anti-Black racism is, as defined by the Movement for Black Lives, a "term used to specifically describe the unique discrimination, violence, and harm imposed on and impacting Black people specifically." In science, technology, engineering, and mathematics (STEM), we have yet to achieve the goal and responsibility to ensure that the field reflects the diversity of our lived experiences. Members of the Women in Molecular Imaging Network (WIMIN) have come together to take a stand on diversity, equity, and inclusion in the field of molecular imaging. We strongly condemn oppression in all its forms and strive to identify and dismantle barriers that lead to inequities in the molecular imaging community and STEM as a whole. In this series coined "Visions" (Antiracism and Allyship in Action), we identify and discuss specific actionable items for improving diversity and representation in molecular imaging and ensuring inclusion of all members of the community, inclusive of race, disability, ethnicity, religion, or LGBTQ+ identity. Although the issues highlighted here extend to other underrecruited and equity-seeking groups, for this first article, we are focusing on one egregious and persistent form of discrimination: anti-Black racism. In this special article, Black women residing in America present their lived experiences in the molecular imaging field and give candid insights into the challenges, frustrations, and hopes of our Black friends and colleagues. While this special article focuses on the experiences of Black women, we would like the readers to Perspectives The perspectives below are representative of collective experiences shared by contributors in this article.