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The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. Results: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce's PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. Conclusion: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD−/−). Twenty-eight wildtype (WT) and 32 H6PD−/− mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca2+-ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD−/− died. At microPET, DXR-H6PD−/− survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD−/− condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity. [ABSTRACT FROM AUTHOR]

Background: In recent years, the interest in Al[18F]F as a labeling agent for Positron Emission Tomography (PET) radiotracers has risen, as it allows for fast and efficient fluorine-18 labeling by harnessing chelation chemistry. The introduction of Restrained Complexing Agent (RESCA) as a chelator has also shown that chelator-based radiolabeling reactions can be performed in mild conditions, making the radiolabeling process attractively more facile than most conventional radiofluorination methods. The aim of the study was to establish optimized conditions for Al[18F]F labeling of Affibody molecules using RESCA as a complexing agent, using Z09591 and Z0185, two Affibody proteins targeting PDGFRβ and TNFα, respectively, as model compounds. Results: The Al[18F]F labeling of RESCA-conjugated Z09591 was tested at different temperatures (rt to 60 °C) and with varying reaction times (12 to 60 min), and optimal conditions were then implemented on RESCA-Z0185. The optimized synthesis method was: 1.5–2.5 GBq of cyclotron produced fluorine-18 were trapped on a QMA cartridge and eluted with saline solution to react with 12 nmol of AlCl3 and form Al[18F]F. The respective RESCA-conjugated Affibody molecule (14 nmol) in NaOAc solution was added to the Al[18F]F solution and left to react at 60 °C for 12 min. The mixture was purified on a NAP5 size exclusion column and then analyzed by HPLC. The entire process took approximately 35 min, was highly reproducible, indicating the efficiency and reliability of the method. The labeled compounds demonstrated retained biological function for their respective targets after purification. Conclusions: We present a general and optimized method for Al[18F]F labeling of RESCA-conjugated Affibody molecules, which can be widely applied to this class of peptide-based imaging agents. Moreover, radiochemical yields were improved when the labeling was conducted at 37 °C or above. In vitro and in vivo assessment of the respective tracers was promising, showing retained binding capacity as well as moderate defluorination, which is usually regarded as a potential downside for RESCA-conjugated tracers. [ABSTRACT FROM AUTHOR]

Background: Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aβ) positron emission tomography (PET) images and neuropsychological assessments. Methods: Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images. Results: There was no significant difference in Aβ deposition between LOD and HC groups. No significant correlation between Aβ burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aβ burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition. Conclusions: These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function. [ABSTRACT FROM AUTHOR]

Hepatocellular cancer (HCC) remained a life-threatening carcinoma. Agents for HCC imaging and therapy were expected to possess different intratumoral retention time. To construct an agent with different intratumoral retention time when applied for tumor imaging or therapy remained great values. A lasialoglycoprotein receptor (ASGPR) targeted lactobionic acid derivative (LABO) was constructed for fluorescent imaging and photodynamic therapy of HCC. 18F labeled LABO (18F-LABO) was developed for PET imaging of HCC. LABO and 18F-LABO showed similar molecular structure. LABO exhibited characteristic of viscosity and concentration-induced intratumoral in-situ self-assembly to expand the intratumoral retention. LABO was non-fluorescent at free stage, but emitted NIR fluorescence and generated irradiation-induced ROS after self-assembly for fluorescent imaging and photodynamic therapy. ASGPR specificity of LABO and 18F-LABO was confirmed using HepG2 cell. Biodistribution and fluorescent imaging confirmed the different tumor retention time of LABO and 18F-LABO when used for photodynamic therapy and PET imaging. PET imaging and photodynamic therapy were performed on HepG2 tumor bearing mice, which revealed that 18F-LABO/LABO could specifically accumulated in the HepG2 tumor for tumor location/inhibition. LABO/18F-LABO with excellent HCC specificity but different intratumoral behaviors showed great values for the PET/NIR imaging and photodynamic therapy for HCC. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. Procedures: TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). Results: The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. Conclusions: We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy. [ABSTRACT FROM AUTHOR]

Introduction Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare neuroectodermal tumor of the nasal cavity and paranasal sinuses. Most of these tumors express somatostatin receptors (SSTRs), providing a potential target for radionuclide imaging with Ga-68 DOTATATE. However, this imaging modality has not been extensively studied in ONB. Methods We conducted a retrospective chart review of 96 endoscopic endonasal skull base surgery cases for ONB performed at our institution between 2000 and 2021. Histo (H) scores were assigned to each tumor and normalized DOTATATE standardized uptake values (nSUVs) were measured as well. Results Nine patients (5 males and 4 females) with ONB were ultimately included in the study. The average age of the patients was 50 years. All ONBs had a positive SSTR2 expression (H-score > 105; mean: 180). All ONBs showed DOTATATE avidity (mean nSUV for ONB: 6.7). However, there was no correlation between H-score and nSUV, with an r2 of 0.24 (p = 0.18). Conclusion Our study shows that SSTR2 expression is found in all ONBs with associated DOTATATE avidity, which may serve as a valuable imaging modality to monitor for recurrent and metastatic disease in ONB. [ABSTRACT FROM AUTHOR]

Introduction: In the current American Joint Committee on Cancer staging system, patients with pelvic nodal metastases are considered stage IV prostate cancer. This study aims to investigate whether men with prostate‐specific membrane antigen positron emission tomography (PSMA PET)‐detected pelvic node‐positive prostate cancer at diagnosis have a better outcome compared to men with node‐positive disease identified on conventional imaging. Methods: This is a retrospective cohort study comparing the outcomes of men with node‐positive prostate cancer and disease confined to the pelvis, staged with conventional versus PSMA PET imaging. Men had to be treated definitively with a combination of androgen deprivation therapy and radiation treatment to the prostate and pelvic lymph nodes. Kaplan–Meier and Cox regression analysis was used to compare biochemical failure‐free survival (BFFS) and overall survival (OS). Results: Seventy‐six men with nodal metastases confined to the pelvis were identified. Fifty‐one were detected with PSMA PET while 25 were staged with conventional imaging. PSMA PET staged patients had a lower proportion of Gleason 8–10 disease (78% vs. 96%) as well as a lower median prostate‐specific antigen (11 ng/mL vs. 26 ng/mL). BFFS at 4 years was 72% with PSMA PET‐detected node‐positive disease vs. 38% with conventionally detected node‐positive disease. Four‐year OS was 93% with PSMA PET staged patients vs. 76% with conventionally staged patients. On multivariate analysis, the PSMA PET staged group was associated with improved BFFS (Adjusted HR = 3.00, 95% CI 1.43, 6.29, P = 0.004) and OS (Adjusted HR = 5.81, 95% CI 1.43, 23.7, P = 0.007). Conclusion: Men with PSMA PET‐detected node‐positive prostate cancer confined to the pelvis have significantly better biochemical control and survival compared to those with node‐positive pelvic disease identified through conventional staging. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging studies in laboratory animals are almost always performed under isoflurane anesthesia to ensure that the subject stays still during the image acquisition. Isoflurane is effective, safe, and easy to use, and it is generally assumed to not have an impact on the imaging results. Motivated by marked differences observed in the brain uptake and metabolism of the PET tracer 3‐[18F]fluoro‐4‐aminopyridine [(18F]3F4AP) between human and nonhuman primate studies, this study investigates the possible effect of isoflurane on this process. Mice received [18F]3F4AP injection while awake or under anesthesia and the tracer brain uptake and metabolism was compared between groups. A separate group of mice received the known cytochrome P450 2E1 inhibitor disulfiram prior to tracer administration. Isoflurane was found to largely abolish tracer metabolism in mice (74.8 ± 1.6 vs. 17.7 ± 1.7% plasma parent fraction, % PF) resulting in a 4.0‐fold higher brain uptake in anesthetized mice at 35 min post‐radiotracer administration. Similar to anesthetized mice, animals that received disulfiram showed reduced metabolism (50.0 ± 6.9% PF) and a 2.2‐fold higher brain signal than control mice. The higher brain uptake and lower metabolism of [18F]3F4AP observed in anesthetized mice compared to awake mice are attributed to isoflurane's interference in the CYP2E1‐mediated breakdown of the tracer, which was confirmed by reproducing the effect upon treatment with the known CYP2E1 inhibitor disulfiram. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia. [ABSTRACT FROM AUTHOR]

The ability of bacteria to recycle exogenous amino acid-based peptides and amino sugars for peptidoglycan biosynthesis was extensively investigated using optical imaging. In particular, fluorescent AeK–NBD was effectively utilized to study the peptidoglycan recycling pathway in Gram-negative bacteria. Based on these promising results, we were inspired to develop the radioactive AeK conjugate [68Ga]Ga-DOTA-AeK for the in vivo localization of bacterial infection using PET/CT. An easy-to-implement radiolabeling procedure for DOTA-AeK with [68Ga]GaCI3 followed by solid-phase purification was successfully established to obtain [68Ga]Ga-DOTA-AeK with a radiochemical purity of ≥95%. [68Ga]Ga-DOTA-AeK showed good stability over time with less protein binding under physiological conditions. The bacterial incorporation of [68Ga]Ga-DOTA-AeK and its fluorescent Aek-NBD analog were investigated in live and heat-killed Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Unfortunately, no conclusive in vitro intracellular uptake of [68Ga]Ga-DOTA-AeK was observed for E. coli or S. aureus live and heat-killed bacterial strains (p > 0.05). In contrast, AeK-NBD showed significantly higher intracellular incorporation in live bacteria compared to the heat-killed control (p < 0.05). Preliminary biodistribution studies of [68Ga]Ga-DOTA-AeK in a dual-model of chronic infection and inflammation revealed limited localization at the infection site with non-specific accumulation in response to inflammatory markers. Finally, our study demonstrates proof that the intracellular incorporation of AeK is necessary for successful bacteria-specific imaging using PET/CT. Therefore, Ga-68 was not a suitable radioisotope for tracing the bacterial uptake of AeK tripeptide, as it required chelation with a bulky metal chelator such as DOTA, which may have limited its active membrane transportation. An alternative for optimization is to explore diverse chemical structures of AeK that would allow for radiolabeling with 18F or 11C. [ABSTRACT FROM AUTHOR]

Purpose: Invasive fungal diseases, such as pulmonary aspergillosis, are common life-threatening infections in immunocompromised patients and effective treatment is often hampered by delays in timely and specific diagnosis. Fungal-specific molecular imaging ligands can provide non-invasive readouts of deep-seated fungal pathologies. In this study, the utility of antibodies and antibody fragments (Fab) targeting β-glucans in the fungal cell wall to detect Aspergillus infections was evaluated both in vitro and in preclinical mouse models. Methods: The binding characteristics of two commercially available β-glucan antibody clones and their respective antigen-binding Fabs were tested using biolayer interferometry (BLI) assays and immunofluorescence staining. In vivo binding of the Zirconium-89 labeled antibodies/Fabs to fungal pathogens was then evaluated using PET/CT imaging in mouse models of fungal infection, bacterial infection and sterile inflammation. Results: One of the evaluated antibodies (HA-βG-Ab) and its Fab (HA-βG-Fab) bound to β-glucans with high affinity (KD = 0.056 & 21.5 nM respectively). Binding to the fungal cell wall was validated by immunofluorescence staining and in vitro binding assays. ImmunoPET imaging with intact antibodies however showed slow clearance and high background signal as well as nonspecific accumulation in sites of infection/inflammation. Conversely, specific binding of [89Zr]Zr-DFO-HA-βG-Fab to sites of fungal infection was observed when compared to the isotype control Fab and was significantly higher in fungal infection than in bacterial infection or sterile inflammation. Conclusions: [89Zr]Zr-DFO-HA-βG-Fab can be used to detect fungal infections in vivo. Targeting distinct components of the fungal cell wall is a viable approach to developing fungal-specific PET tracers. [ABSTRACT FROM AUTHOR]

The arginine-vasopressin (AVP) hormone plays a pivotal role in regulating various physiological processes, such as hormone secretion, cardiovascular modulation, and social behavior. Recent studies have highlighted the V1a receptor as a promising therapeutic target. In-depth insights into V1a receptor-related pathologies, attained through in vivo imaging and quantification in both peripheral organs and the central nervous system (CNS), could significantly advance the development of effective V1a inhibitors. To address this need, we develop a novel V1a-targeted positron emission tomography (PET) ligand, [18F]V1A-2303 ([18F] 8), which demonstrates favorable in vitro binding affinity and selectivity for the V1a receptor. Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies, autoradiography, biodistribution assessments. Furthermore, [18F] 8 was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity, whole-body distribution, and kinetic properties. Our research indicated [18F] 8 as a valuable tool for noninvasively studying V1a receptors in peripheral organs, and as a foundational element for the development of next-generation, brain-penetrant ligands specifically designed for the CNS. This work described the synthesis and evaluation of a novel 18F-labeled vasopressin 1a receptor PET ligand, which showed peripheral binding specificity and could cross the blood‒brain barrier in non-human primates. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose of review: This article aims to illustrate the current state of investigations and management of liver metastases in patients with Neuroendocrine Neoplasms. Neuroendocrine tumours (NETs) are rising in incidence globally and have become the second most prevalent gastrointestinal malignancy in UK and USA. Frequently, patients have metastatic disease at time of presentation. The liver is the most common site of metastases for gastro-enteropancreatic NETs. Characterisation of liver metastases with imaging is important to ensure disease is not under-staged. Recent Findings: Magnetic resonance imaging and positron emission tomography are now becoming standard of care for imaging liver metastases. There is an increasing armamentarium of therapies available for management of NETs and loco-regional therapy for liver metastases. The data supporting surgical and loco-regional therapy is reviewed with focus on role of liver transplantation. Summary: It is important to use appropriate imaging and classification of NET liver metastases. It is key that decisions regarding approach to treatment is undertaken in a multidisciplinary team and that individualised approaches are considered for management of patients with metastatic NETs. [ABSTRACT FROM AUTHOR]

In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated the effect of glutamate on the Alzheimers disease (AD) brain. Human post-mortem AD brain slices of the frontal cortex and anterior cingulate were incubated with [3H]MK-801 and adjacent sections were tested for Aβ and Tau. The binding of [3H]MK-801 was measured in the absence and presence of glutamate and glycine. Increased [3H]MK-801 binding in AD brains was observed at baseline and in the presence of glutamate, indicating a significant increase (>100%) in glutamate-induced NMDA ion channel activity in AD brains compared to cognitively normal brains. The glycine effect was lower, suggesting a decrease of the co-agonist effect of glutamate and glycine in the AD brain. Our preliminary findings suggest that the targeting of the NMDA ion channel as well as the glutamate site may be appropriate in the diagnosis and treatment of AD. However, the low baseline levels of [3H]MK-801 binding in the frontal cortex and anterior cingulate in the absence of glutamate and glycine indicate significant hurdles for in vivo imaging probe development and validation.

Abstract Background In recent years, the interest in Al[18F]F as a labeling agent for Positron Emission Tomography (PET) radiotracers has risen, as it allows for fast and efficient fluorine-18 labeling by harnessing chelation chemistry. The introduction of Restrained Complexing Agent (RESCA) as a chelator has also shown that chelator-based radiolabeling reactions can be performed in mild conditions, making the radiolabeling process attractively more facile than most conventional radiofluorination methods. The aim of the study was to establish optimized conditions for Al[18F]F labeling of Affibody molecules using RESCA as a complexing agent, using Z09591 and Z0185, two Affibody proteins targeting PDGFRβ and TNFα, respectively, as model compounds. Results The Al[18F]F labeling of RESCA-conjugated Z09591 was tested at different temperatures (rt to 60 °C) and with varying reaction times (12 to 60 min), and optimal conditions were then implemented on RESCA-Z0185. The optimized synthesis method was: 1.5–2.5 GBq of cyclotron produced fluorine-18 were trapped on a QMA cartridge and eluted with saline solution to react with 12 nmol of AlCl3 and form Al[18F]F. The respective RESCA-conjugated Affibody molecule (14 nmol) in NaOAc solution was added to the Al[18F]F solution and left to react at 60 °C for 12 min. The mixture was purified on a NAP5 size exclusion column and then analyzed by HPLC. The entire process took approximately 35 min, was highly reproducible, indicating the efficiency and reliability of the method. The labeled compounds demonstrated retained biological function for their respective targets after purification. Conclusions We present a general and optimized method for Al[18F]F labeling of RESCA-conjugated Affibody molecules, which can be widely applied to this class of peptide-based imaging agents. Moreover, radiochemical yields were improved when the labeling was conducted at 37 °C or above. In vitro and in vivo assessment of the respective tracers was promising, showing retained binding capacity as well as moderate defluorination, which is usually regarded as a potential downside for RESCA-conjugated tracers. Graphical abstract

Abstract Background Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aβ) positron emission tomography (PET) images and neuropsychological assessments. Methods Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images. Results There was no significant difference in Aβ deposition between LOD and HC groups. No significant correlation between Aβ burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aβ burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition. Conclusions These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function.

Abstract Hepatocellular cancer (HCC) remained a life-threatening carcinoma. Agents for HCC imaging and therapy were expected to possess different intratumoral retention time. To construct an agent with different intratumoral retention time when applied for tumor imaging or therapy remained great values. A lasialoglycoprotein receptor (ASGPR) targeted lactobionic acid derivative (LABO) was constructed for fluorescent imaging and photodynamic therapy of HCC. 18F labeled LABO (18F-LABO) was developed for PET imaging of HCC. LABO and 18F-LABO showed similar molecular structure. LABO exhibited characteristic of viscosity and concentration-induced intratumoral in-situ self-assembly to expand the intratumoral retention. LABO was non-fluorescent at free stage, but emitted NIR fluorescence and generated irradiation-induced ROS after self-assembly for fluorescent imaging and photodynamic therapy. ASGPR specificity of LABO and 18F-LABO was confirmed using HepG2 cell. Biodistribution and fluorescent imaging confirmed the different tumor retention time of LABO and 18F-LABO when used for photodynamic therapy and PET imaging. PET imaging and photodynamic therapy were performed on HepG2 tumor bearing mice, which revealed that 18F-LABO/LABO could specifically accumulated in the HepG2 tumor for tumor location/inhibition. LABO/18F-LABO with excellent HCC specificity but different intratumoral behaviors showed great values for the PET/NIR imaging and photodynamic therapy for HCC. Graphical Abstract

The arginine-vasopressin (AVP) hormone plays a pivotal role in regulating various physiological processes, such as hormone secretion, cardiovascular modulation, and social behavior. Recent studies have highlighted the V1a receptor as a promising therapeutic target. In-depth insights into V1a receptor-related pathologies, attained through in vivo imaging and quantification in both peripheral organs and the central nervous system (CNS), could significantly advance the development of effective V1a inhibitors. To address this need, we develop a novel V1a-targeted positron emission tomography (PET) ligand, [18F]V1A-2303 ([18F]8), which demonstrates favorable in vitro binding affinity and selectivity for the V1a receptor. Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies, autoradiography, biodistribution assessments. Furthermore, [18F]8 was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity, whole-body distribution, and kinetic properties. Our research indicated [18F]8 as a valuable tool for noninvasively studying V1a receptors in peripheral organs, and as a foundational element for the development of next-generation, brain-penetrant ligands specifically designed for the CNS.

A 76-year-old man with a history of malignant pleural mesothelioma treated with pembrolizumab underwent FDG-PET/CT for restaging. The images demonstrated FDG uptake overlying the right hepatic and splenic artery, which were new from the previous FDG-PET/CT 2.5 years prior before the patient started pembrolizumab, suspicious for vasculitis. A follow-up MRI supported the diagnosis with evidence of celiac, splenic, common hepatic, and right hepatic artery involvement. Pembrolizumab was discontinued and the patient received a short course of oral glucocorticoids. Subsequent FDG-PET/CT performed 14 months after initiation of treatment for vasculitis demonstrated resolution of vasculitis. Immune checkpoint inhibitors can cause vasculitis, which can be recognized on FDG-PET/CT and lead to appropriate treatment.

Abstract Background The cysteine-aspartic acid protease caspase-3 is recognized as the main executioner of apoptosis in cells responding to specific extrinsic and intrinsic stimuli. Caspase-3 represents an interesting biomarker to evaluate treatment response, as many cancer therapies exert their effect by inducing tumour cell death. Previously developed caspase-3 PET tracers were unable to reach routine clinical use due to low tumour uptake or lack of target selectivity, which are two important requirements for effective treatment response evaluation in cancer patients. Therefore, the goal of this study was to develop and preclinically evaluate novel caspase-3-selective activity-based probes (ABPs) for apoptosis imaging. Results A library of caspase-3-selective ABPs was developed for tumour apoptosis detection. In a first attempt, the inhibitor Ac-DW3-KE (Ac-3Pal-Asp-βhLeu-Phe-Asp-KE) was 18F-labelled on the N-terminus to generate a radiotracer that was incapable of adequately detecting an increase in apoptosis in vivo. The inability to effectively detect active caspase-3 in vivo was likely attributable to slow binding, as demonstrated with in vitro inhibition kinetics. Hence, a second generation of caspase-3 selective ABPs was developed based on the Ac-ATS010-KE (Ac-3Pal-Asp-Phe(F5)-Phe-Asp-KE) with greatly improved binding kinetics over Ac-DW3-KE. Our probes based on Ac-ATS010-KE were made by modifying the N-terminus with 6 different linkers. All the linker modifications had limited effect on the binding kinetics, target selectivity, and pharmacokinetic profile in healthy mice. In an in vitro apoptosis model, the least hydrophilic tracer [18F]MICA-316 showed an increased uptake in apoptotic cells in comparison to the control group. Finally, [18F]MICA-316 was tested in an in vivo colorectal cancer model, where it showed a limited tumour uptake and was unable to discriminate treated tumours from the untreated group, despite demonstrating that the radiotracer was able to bind caspase-3 in complex mixtures in vitro. In contrast, the phosphatidylethanolamine (PE)-binding radiotracer [99mTc]Tc-duramycin was able to recognize the increased cell death in the disease model, making it the best performing treatment response assessment tracer developed thus far. Conclusions In conclusion, a novel library of caspase-3-binding PET tracers retaining similar binding kinetics as the original inhibitor was developed. The most promising tracer, [18F]MICA-316, showed an increase uptake in an in vitro apoptosis model and was able to selectively bind caspase-3 in apoptotic tumour cells. In order to distinguish therapy-responsive from non-responsive tumours, the next generation of caspase-3-selective ABPs will be developed with higher tumour accumulation and in vivo stability.

Abstract Background Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and early detection is critical to improve the clinical outcome of this disease. In this study, the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 (an investigational medicinal product) positron emission tomography (PET) imaging in UM xenografts and UM patients were evaluated. The cell uptake, cell binding ability and in vitro stability of [18F]AlF-NOTA-PRGD2 were evaluated in 92-1 UM cell line. MicroPET imaging and biodistribution study of [18F]AlF-NOTA-PRGD2 were conducted in 92-1 UM xenografts. Then, UM patients were further recruited for evaluating the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 PET imaging (approval no. NCT02441972 in clinicaltrials.gov). In addition, comparison of [18F]AlF-NOTA-PRGD2 and 18F-labelled fluorodeoxyglucose ([18F]FDG) PET imaging in UM xenografts and UM patients were conducted. Results The in vitro data showed that [18F]AlF-NOTA-PRGD2 had a high cell uptake, cell binding ability and in vitro stability in 92-1 UM cell line. The in vivo data indicated that 92-1 UM tumors were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer in the subcutaneous and ocular primary UM xenografts model at 60 min post-injection. And the tumor uptake of the tracer was 2.55 ± 0.44%ID/g and 1.73 ± 0.15%ID/g at these two tissue locations respectively, at 7 days after animal model construction. The clinical data showed that tumors in UM patients were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer at 60 min post-injection. In addition, [18F]AlF-NOTA-PRGD2 tracer showed higher sensitivity and specificity for PET imaging in UM xenografts and UM patients compared to [18F]FDG tracer. Conclusion [18F]AlF-NOTA-PRGD2 PET imaging may be a more preferred approach in the diagnosis of primary UM compared to [18F]FDG PET imaging. Additionally, due to the high tumor-to-background ratio, [18F]AlF-NOTA-PRGD2 PET imaging seems also to be applicable for the diagnosis of UM patients with liver metastasis. Trial registration: ClinicalTrials.gov: NCT02441972, Registered 1 January 2012, https://clinicaltrials.gov/study/NCT02441972 .

Deep neural networks trained on labeled medical data face major challenges owing to the economic costs of data acquisition through expensive medical imaging devices, expert labor for data annotation, and large datasets to achieve optimal model performance. The heterogeneity of diseases, such as Alzheimer's disease, further complicates deep learning because the test cases may substantially differ from the training data, possibly increasing the rate of false positives. We propose a reconstruction-based self-supervised anomaly detection model to overcome these challenges. It has a dual-subnetwork encoder that enhances feature encoding augmented by skip connections to the decoder for improving the gradient flow. The novel encoder captures local and global features to improve image reconstruction. In addition, we introduce an entropy-based image conversion method. Extensive evaluations show that the proposed model outperforms benchmark models in anomaly detection and classification using an encoder. The supervised and unsupervised models show improved performances when trained with data preprocessed using the proposed image conversion method.

Introduction Methods Results Conclusion Rarely, appendiceal neuroendocrine tumours (NET) are an incidental finding when an appendicectomy is undertaken for suspected appendicitis. The role of further imaging in this setting is poorly defined. Positron emission tomography (PET) using 68Ga‐DOTATATE is requested to evaluate post‐surgical status, however, there is little evidence to guide how it should be employed. The aims of this project are to: (i) characterize 68Ga‐DOTATATE PET findings in patients with incidental appendiceal NETs and (ii) discuss how these data might inform post‐surgical imaging with PET.We reviewed 47 PET scans in 30 patients, undertaken from 2009 to 2018. Scintigraphic findings, histopathological characteristics of the initial appendiceal lesion and medical records were reviewed.Most patients (n = 15) had small (<10 mm) appendiceal NETs with low grade (Ki67 < 2%) features. Eight patients had tumours between 10 and 20 mm, and seven had tumours >20 mm. Goblet cell features were identified in two patients. Three positive PET scans were reported in one patient with an index tumour measuring 40 mm and Ki67 < 2%. The remaining 29 patients had 44 negative scans. Clinical outcome data were available in 27 patients (mean follow‐up time 57 months; range 6–123 months). There was no evidence of recurrent neuroendocrine disease at the time of the last follow‐up.These data indicate that in most cases, post‐surgical 68Ga‐DOTATATE PET is negative in patients with incidentally detected appendiceal NETs. Clinical outcome data suggest that 68Ga‐DOTATATE PET should be reserved for patients with large tumours (>20 mm) or those displaying goblet cell features. [ABSTRACT FROM AUTHOR]

As well known in bioactives delivery and cancer/inflammation theranostics, polycations have recently extended their biomedical potentials in reducing visceral fat, embolizing body fluid, modulating blood coagulation, and ameliorating hyperammonemia. However, positive charges that dominate various action mechanisms, often raise risks in biosafety concerns. Also, the lack of intrinsic imaging properties of polycations makes it challenging to uncover their pharmacokinetic profiles in living objects. Herein, dopamine conjugation is demonstrated controllable and highly efficient in boosting the fluorescence or even white color emission of various polycations including hyperbranched poly(amido amine) (HPAA), polyethyleneimine and poly‐L‐lysine. By shielding partial surface positive charges, increasing hydrophobicity, and inducing aqueous self‐assembly, dopamine conjugation can significantly enhance the biocompatibility and decrease the toxicity and immunogenicity of polycations. Furthermore, the catechol‐metal binding interaction facilitates the accessibility of polycation‐based positron emission tomography (PET) probes. Different tissue uptake and biodistributions of gallium‐68‐radiolabeled HPAA before and after dopamine conjugation indicate that PET imaging can be a useful supplement to evaluate the dynamic toxicities of polycations. [ABSTRACT FROM AUTHOR]

Background: The cysteine-aspartic acid protease caspase-3 is recognized as the main executioner of apoptosis in cells responding to specific extrinsic and intrinsic stimuli. Caspase-3 represents an interesting biomarker to evaluate treatment response, as many cancer therapies exert their effect by inducing tumour cell death. Previously developed caspase-3 PET tracers were unable to reach routine clinical use due to low tumour uptake or lack of target selectivity, which are two important requirements for effective treatment response evaluation in cancer patients. Therefore, the goal of this study was to develop and preclinically evaluate novel caspase-3-selective activity-based probes (ABPs) for apoptosis imaging. Results: A library of caspase-3-selective ABPs was developed for tumour apoptosis detection. In a first attempt, the inhibitor Ac-DW3-KE (Ac-3Pal-Asp-βhLeu-Phe-Asp-KE) was 18F-labelled on the N-terminus to generate a radiotracer that was incapable of adequately detecting an increase in apoptosis in vivo. The inability to effectively detect active caspase-3 in vivo was likely attributable to slow binding, as demonstrated with in vitro inhibition kinetics. Hence, a second generation of caspase-3 selective ABPs was developed based on the Ac-ATS010-KE (Ac-3Pal-Asp-Phe(F5)-Phe-Asp-KE) with greatly improved binding kinetics over Ac-DW3-KE. Our probes based on Ac-ATS010-KE were made by modifying the N-terminus with 6 different linkers. All the linker modifications had limited effect on the binding kinetics, target selectivity, and pharmacokinetic profile in healthy mice. In an in vitro apoptosis model, the least hydrophilic tracer [18F]MICA-316 showed an increased uptake in apoptotic cells in comparison to the control group. Finally, [18F]MICA-316 was tested in an in vivo colorectal cancer model, where it showed a limited tumour uptake and was unable to discriminate treated tumours from the untreated group, despite demonstrating that the radiotracer was able to bind caspase-3 in complex mixtures in vitro. In contrast, the phosphatidylethanolamine (PE)-binding radiotracer [99mTc]Tc-duramycin was able to recognize the increased cell death in the disease model, making it the best performing treatment response assessment tracer developed thus far. Conclusions: In conclusion, a novel library of caspase-3-binding PET tracers retaining similar binding kinetics as the original inhibitor was developed. The most promising tracer, [18F]MICA-316, showed an increase uptake in an in vitro apoptosis model and was able to selectively bind caspase-3 in apoptotic tumour cells. In order to distinguish therapy-responsive from non-responsive tumours, the next generation of caspase-3-selective ABPs will be developed with higher tumour accumulation and in vivo stability. [ABSTRACT FROM AUTHOR]

Cannabinoid subtype 1 receptors (CB1Rs) are an important class of G proteincoupled receptors (GPCRs) belonging to the endocannabinoid system. CB1Rs play a crucial modulatory role in the functioning of other neurotransmitter systems and are involved in a wide range of physiological functions and dysfunctions; thus, they are considered one of the most important targets for drug development, as well as diagnostic purposes. Despite this, only a few molecules targeting this receptor are available on the pharmaceutical market, thus emphasizing the need to gain a deeper understanding of the complex activation pathways of CB1Rs and how they regulate diseases. As part of this review, we provide an overview of pharmacological and imaging tools useful for detecting CB1Rs. Herein, we summarize the derivations of cannabinoids and terpenoids with fluorescent compounds, radiotracers, or photochromic motifs. CB1Rs' molecular probes may be used in vitro and, in some cases, in vivo for investigating and exploring the roles of CB1Rs together with the starting point for the development of CB1R-targeted drugs. [ABSTRACT FROM AUTHOR]

Disorganized behavior is a primary sign of schizophrenia. Yet it is not unique to schizophrenia. Recently, there has been a growing understanding that endogenous mental disorders could be a prodromal stage of neurodegenerative dementia. As a result, the connection between endogenous mental disorders and dementia has become a subject of significant interest. In the present study, a 49-year-old female with schizophrenia since the age of 17 was diagnosed with early-onset Alzheimer's disease after a detailed examination with PET and cerebrospinal fluid, despite suspicion of organic disease due to progressive forgetfulness, abnormal behavior and delusions. Schizophrenia is not the only disorder in which disorganized behavior is seen. When such a clinical phenomenon develops, other possible causes should be considered. Dementia is one of the most important of these causes. In a psychiatric disorder with disorganized behavior, other possible causes, especially dementia, should be considered. [ABSTRACT FROM AUTHOR]

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = –0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = –0.035(0.009), p = 0.001), inferior temporal (β (SE) = –0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = –0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities. [ABSTRACT FROM AUTHOR]

Positron Emission Tomography (PET) is an important part of the medical imaging field which is continually exploring novel biological targets as exemplified by PET imaging of neuroinflammation. Due to limitations stemming from either sub‐optimal biological targets or a lack of available selective radiotracers, alternative biomarkers and PET imaging agent candidates are considered. One such possible target is microRNA (miRNA) and herein, we discuss the potential of miRNA for PET imaging. With the aim of addressing key strategies for imaging miRNA with PET, we identify three distinct approaches as follows: small molecules directly targeting miRNA, small molecules indirectly targeting Argonaute 2 (AGO2)‐protein complexes, and direct chemical modification of antisense oligonucleotides. The radiosynthetic approaches are based on the methods of direct radiolabelling of respective antisense oligonucleotides and several examples are described herein, showcasing the potential of miRNA in PET imaging. Whilst these approaches offer different radiolabelling strategies, application of these radiolabelled molecules towards PET imaging of miRNA are scarce with only one, limited example applied to bone remodeling reported in the literature. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. Methods: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. Results: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. Conclusion: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers. [ABSTRACT FROM AUTHOR]

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile. [ABSTRACT FROM AUTHOR]

Gold nanoclusters (AuNCs) have great potential to enhance tumor radiotherapy. However, their tumor accumulation efficiency is relatively low due to their ultrasmall size. In this study, an acid-responsive tumor targeting strategy is proposed by introducing l-cystine onto glutathione-coated AuNCs (l-Cys/GSH@AuNCs). l-Cys/GSH@AuNCs are able to swiftly respond to acid conditions to assembly into large clusters and aggregate in lysosomes upon internalization by tumor cells, leading to increased accumulation in cancer cells. Moreover, metal radioisotope 89Zr and 68Ga could be doped into AuNCs with high efficiency and stability. PET imaging of tumor-bearing mice reveals that radiolabeled l-Cys/GSH@AuNCs are primarily eliminated via the renal system but could respond to tumor acid microenvironment to accumulate in tumor high efficiently and remain in tumors for a long time period. As a result, radiotherapy in combination with l-Cys/GSH@AuNCs completely suppresses tumor growth. Our study paves a way for AuNCs to enhance tumor radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and early detection is critical to improve the clinical outcome of this disease. In this study, the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 (an investigational medicinal product) positron emission tomography (PET) imaging in UM xenografts and UM patients were evaluated. The cell uptake, cell binding ability and in vitro stability of [18F]AlF-NOTA-PRGD2 were evaluated in 92-1 UM cell line. MicroPET imaging and biodistribution study of [18F]AlF-NOTA-PRGD2 were conducted in 92-1 UM xenografts. Then, UM patients were further recruited for evaluating the diagnostic effectiveness of [18F]AlF-NOTA-PRGD2 PET imaging (approval no. NCT02441972 in clinicaltrials.gov). In addition, comparison of [18F]AlF-NOTA-PRGD2 and 18F-labelled fluorodeoxyglucose ([18F]FDG) PET imaging in UM xenografts and UM patients were conducted. Results: The in vitro data showed that [18F]AlF-NOTA-PRGD2 had a high cell uptake, cell binding ability and in vitro stability in 92-1 UM cell line. The in vivo data indicated that 92-1 UM tumors were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer in the subcutaneous and ocular primary UM xenografts model at 60 min post-injection. And the tumor uptake of the tracer was 2.55 ± 0.44%ID/g and 1.73 ± 0.15%ID/g at these two tissue locations respectively, at 7 days after animal model construction. The clinical data showed that tumors in UM patients were clearly visualized with the [18F]AlF-NOTA-PRGD2 tracer at 60 min post-injection. In addition, [18F]AlF-NOTA-PRGD2 tracer showed higher sensitivity and specificity for PET imaging in UM xenografts and UM patients compared to [18F]FDG tracer. Conclusion: [18F]AlF-NOTA-PRGD2 PET imaging may be a more preferred approach in the diagnosis of primary UM compared to [18F]FDG PET imaging. Additionally, due to the high tumor-to-background ratio, [18F]AlF-NOTA-PRGD2 PET imaging seems also to be applicable for the diagnosis of UM patients with liver metastasis. Trial registration: ClinicalTrials.gov: NCT02441972, Registered 1 January 2012, https://clinicaltrials.gov/study/NCT02441972. [ABSTRACT FROM AUTHOR]

Background: 18-F fluoro-2-deoxy-D-glucose (18F-FDG) is the most common tracer in whole-body positron emission tomography (PET) imaging for cancer. The diagnostic information gained from a 18F-FDG is beneficial, but the administration of radioactive material always comes with an increased risk of secondary cancer. The objective of this paper was to calculate the effective dose for 18F-FDG injected patients considering the specific contribution from positron slowing down, positron annihilation, and electron capture mechanisms. Materials and Methods: The dose for various organs was estimated by using the Monte Carlo (MC) method. The Medical Internal Radiation Dose (MIRD) female phantom was used for the simulations and the effective doses to various organs from internal exposure from a 18F-FDG injection were calculated using a biokinetic model and International Commission on Radiological Protection (ICRP) publication 128 provided data. Calculated doses were compared with measured doses found in published studies. Results: The dose for each organ is dependent on the 18F decay mode. The total effective dose is 6.73 mSv when the administered activity is 185 MBq. Positron annihilation leads to the highest average effective dose at 3.57 mSv. The effective doses for positron slowing and electron capture gammas are 2.99 and 0.17 mSv, respectively. The urinary bladder, followed by the brain and heart, have the highest absorbed doses. The calculated doses for a female patient are in good agreement with published measured data. Conclusions: The results presented here can be used to scale the dose measured by a dosimeter to estimate the patient's absorbed dose. Tracking the cumulative effective dose from medical procedures is an important aspect of managing the care of cancer patients to ensure regulatory limits are not exceeded. [ABSTRACT FROM AUTHOR]

The objective of this study is to provide a positron emission tomography (PET) imaging modality targeting vascular endothelial growth factor receptors (VEGFR) for the early noninvasive detection and assessment of pulmonary arterial hypertension (PAH) severity. To validate the effectiveness of the [18F]VEGFR PET tracer, we utilized a monocrotaline (MCT)‐induced PAH rat model. Molecular optical imaging, using a Cy5.5‐conjugated VEGFR targeting agent, was employed to demonstrate the uptake of the agent at pulmonary arterioles, correlating with the onset and progression of PAH. Histological examinations of the MCT‐PAH rat lung revealed a significant correlation between VEGFR2 expression and the pathogenesis of PAH. Molecular optical imaging demonstrated heightened uptake of the Cy5.5‐conjugated VEGFR targeting agent at pulmonary arterioles, corresponding with the onset and progression of PAH. [18F]VEGFR PET showed increased lung uptake detectable in early‐stage PAH before increase in pulmonary artery pressures, and this uptake correlated with increased PAH severity. Moreover, when compared to [18F]FDG PET, [18F]VEGFR PET exhibited markedly lower background cardiac signal, enhancing imaging sensitivity for lung abnormalities. Our study provides a compelling evidence for the potential utility of the innovative [18F]VEGFR PET tracer, in non‐invasively detecting early signs of PAH, and monitoring its progression. The observed correlations between VEGFR2 expression, molecular optical imaging results, and [18F]VEGFR PET findings support the use of this tracer for early detection, and assessment of PAH severity. The lower background cardiac signal observed with [18F]VEGFR PET further enhances its imaging sensitivity, emphasizing its potential clinical significance. [ABSTRACT FROM AUTHOR]

A new automated radiosynthesis of [11C]2‐(2,6‐difluoro‐4‐((2‐(N‐methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)‐compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use. [ABSTRACT FROM AUTHOR]

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient's chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (68Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [68Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [68Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC50 value being about 867 nM. The biodistribution and PET/CT studies revealed that [68Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [68Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression. [ABSTRACT FROM AUTHOR]

Purpose: Predicting recurrence following stereotactic body radiotherapy (SBRT) for non‐small cell lung cancer provides important information for the feasibility of the individualized radiotherapy and allows to select the appropriate treatment strategy based on the risk of recurrence. In this study, we evaluated the performance of both machine learning models using positron emission tomography (PET) and computed tomography (CT) radiomic features for predicting recurrence after SBRT. Methods: Planning CT and PET images of 82 non‐small cell lung cancer patients who performed SBRT at our hospital were used. First, tumors were delineated on each CT and PET of each patient, and 111 unique radiomic features were extracted, respectively. Next, the 10 features were selected using three different feature selection algorithms, respectively. Recurrence prediction models based on the selected features and four different machine learning algorithms were developed, respectively. Finally, we compared the predictive performance of each model for each recurrence pattern using the mean area under the curve (AUC) calculated following the 0.632+ bootstrap method. Results: The highest performance for local recurrence, regional lymph node metastasis, and distant metastasis were observed in models using Support vector machine with PET features (mean AUC = 0.646), Naive Bayes with PET features (mean AUC = 0.611), and Support vector machine with CT features (mean AUC = 0.645), respectively. Conclusions: We comprehensively evaluated the performance of prediction model developed for recurrence following SBRT. The model in this study would provide information to predict the recurrence pattern and assist in making treatment strategies. [ABSTRACT FROM AUTHOR]

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the impact of the use of varying input parameters on resulting bone plasma clearance (Ki) and other kinetic modelling parameters in a group of patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). Methods: Raw PET/CT data and blood data were systematically analyzed using five different VOIs for the input functions in the left ventricle and in the thoracic aorta. Standardized VOIs were placed in four thoracic vertebrae and the results pooled and averaged. The basic image-derived input functions (IDIFs) were corrected for partial volume effect and spill-over and modified by substitution of the terminal image exponential with the corresponding plasma-exponentials derived from blood samples. Ki was then calculated using both a non-linear regression (NLR) analysis and a graphical Patlak analysis and compared. Results: Our original results were reproducible with an inter-observer difference of approximately 6%. The correction factors varied with the VOI volumes from 0.73 ± 0.17 for the largest LV-VOI (48.7 ± 25.3 cm³) to 0.99 ± 0.10 for the AOVOI (3.4 ± 1.2 cm³). The mean NLR-Ki results varied between 0.0378 ± 0.0112 and 0.0432 ± 0.0095 ml/min ml-1 with a fixed vB and 0.0408 ± 0.0111 and 0.045 ± 0.0102 ml/min ml-1 with a free-fitted vB. The corresponding Patl-Kiresults varied between 0.0302 ± 0.0071 and 0.0325 ± 0.0070 ml/min ml-1, having lesser differences and variances. The input functions with least variance and mean differences compared with NLR results were derived from the left ventricle with a VOI volume of 19.2 ± 11.3 cm³ corrected for PVE and Bg with a mean Ki-difference: 0.0097 ± 0.0370 ml/min ml-1 and 95% confidence limits (-0.023 to 0.004). Conclusions: Our results indicated that a VOI with a volume of approximately 20 cm³ with a correction factor of 0.83 ± 0.13 results in Patlak results with the least variance and difference compared with the NLR results. The use of free-fitted vB in the NLR analysis showed the most robust results in all input series. The Patlak results were in comparison generally lower than the NLR results (-17.3% to -23.4%) but very robust across the various input series and with results comparable to previously published data and are therefore recommended for future analysis. [ABSTRACT FROM AUTHOR]

Discussed are two picolinate appended bispidine ligands (3,7‐diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis‐pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu‐bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu‐labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl‐NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS‐functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor‐bearing mice showed specific accumulation of the 64Cu‐labeled TMs in PSCA‐ and FAP‐overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors. [ABSTRACT FROM AUTHOR]

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the 68Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for 68Ga-labeling. The 68Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the 68Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the 68Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [1⁸F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan–kynurenine pathway as a therapeutic target for treating NF1. [ABSTRACT FROM AUTHOR]

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probe 's targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation. [ABSTRACT FROM AUTHOR]

Deep neural networks trained on labeled medical data face major challenges owing to the economic costs of data acquisition through expensive medical imaging devices, expert labor for data annotation, and large datasets to achieve optimal model performance. The heterogeneity of diseases, such as Alzheimer's disease, further complicates deep learning because the test cases may substantially differ from the training data, possibly increasing the rate of false positives. We propose a reconstruction‐based self‐supervised anomaly detection model to overcome these challenges. It has a dual‐subnetwork encoder that enhances feature encoding augmented by skip connections to the decoder for improving the gradient flow. The novel encoder captures local and global features to improve image reconstruction. In addition, we introduce an entropy‐based image conversion method. Extensive evaluations show that the proposed model outperforms benchmark models in anomaly detection and classification using an encoder. The supervised and unsupervised models show improved performances when trained with data preprocessed using the proposed image conversion method. [ABSTRACT FROM AUTHOR]

Diagnostic reference levels (DRLs) are an important tool for controlling radiation exposure and ensuring safety in medical applications. In Thailand, DRL data have been gathered and established for nuclear medicine diagnostics since 2021. However, there is a lack of information on PET imaging examinations. At the National Cyclotron and PET Scan Centre, Chulabhorn Hospital, radiopharmaceuticals are produced for medical imaging and research, and a wide range of PET/CT and PET/MRI examinations are performed. Our objective was to investigate the administered activity of radiopharmaceuticals in patients undergoing PET imaging, especially the existing data on DRLs in medical diagnostic imaging. Methods: This was a retrospective study on nuclear medicine patients at the National Cyclotron and PET Scan Centre in 2023. Statistical analysis, including the mean and the 75th percentile values, was conducted to determine DRLs according to the International Commission on Radiological Protection guidelines. Results: The center performed 8,711 PET/CT and PET/MRI studies with 13 protocols in 2023. The most commonly administered activity was 18F-FDG in oncology and neurology examinations, with DRLs of 186.11 and 136.16 MBq, respectively. These values were notably almost twice lower than several reports in other countries. Conclusion: There is a lack of comprehensive data on most DRLs for PET imaging at this center because of the nonwidespread use of several radiopharmaceuticals. However, the lower DRLs for 18F-FDG can highlight the need for ongoing investigation toward the establishment of local DRLs, as well as assurance on the safety and efficiency of radiation used in nuclear medicine. [ABSTRACT FROM AUTHOR]

225Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The in vivo generator 134Ce/134La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides 225Ac and 227Th. In this report, we detail efficient radiolabeling methods using the 225Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG4-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding 225Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with 134Ce/134La in NH4OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of 134Ce-DOTA/MACROPA.NH2 complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free 134CeCl3 In vivo, preclinical imaging of 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for 134Ce/225Ac-MACROPA-PEG4-YS5 conjugates. Results: 134Ce-MACROPA.NH2 demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for 134Ce/225Ac-DOTA/MACROPA. NH2 conjugates in comparison to free 134CeCl3 confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG4-YS5-that the daughter 134La was expelled from the chelate after the decay of parent 134Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of 134Ce-MACROPA.NH2, 134Ce-DOTA and 134Ce-MACROPA-PEG4-YS5 corroborated well with the respective 225Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for 134Ce/134La-labeled small-molecule and antibody agents. The similar 225Ac and 134Ce/134La-chemical and pharmacokinetic characteristics suggest that the 134Ce/134La pair may act as a PET imaging surrogate for 225Ac-based radioligand therapies.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.