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Tumor metabolism is a hallmark of cancer, yet cellular heterogeneity within the tumor microenvironment presents a significant challenge, as bulk analysis masks the diverse metabolic profiles of individual cell populations. This complexity complicates our understanding of [ 18 F]FDG uptake by distinct cell types in the tumor microenvironment. This study aims to investigate [ 18 F]FDG uptake at the single-cell level in the lung of Kirsten rat sarcoma virus-driven cancer mouse models using the novel technique radio-flow cytometry (radioFlow). Methods: Two Kirsten rat sarcoma virus-driven lung cancer mouse models were injected with [ 18 F]FDG for small-animal PET/CT and subsequent fluorescence-activated cell sorting of the lung. For radioFlow, the sorted cell fractions were then measured in a γ-counter and their radioactivity was normalized to the number of cells. Results: RadioFlow analysis of the lung tissue of both models showed a robust cell type-specific uptake pattern across experiments. Our key findings indicate that the [ 18 F]FDG PET signal predominantly derives from immune cells (CD45 + , F4/80 - , 78.3% ± 6.6%; macrophage, 13.9% ± 4.3%), whereas tumor cells contributed only with 2.8% ± 1.0%, similar to the uptake of structural cells (CD45 - ; tumor cells, 5.0% ± 2.3%). Normalization showed that macrophages exhibited the highest glucose metabolism in both tumor models (57% ± 8%), followed by the remaining immune cells (27% ± 3%). Conclusion: These findings highlight the critical influence of immune cell metabolism on [ 18 F]FDG imaging, emphasizing the need to account for immune contributions when interpreting [ 18 F]FDG imaging in cancer., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [ 11 C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = -0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = -0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing., Competing Interests: Competing interests: RL received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, and Siemens Healthineers. All other authors report no conflict of interest in relation to this study., (© 2024. The Author(s).)

The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood-brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pK a values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pK a values are often missing and published experimental pK a values are limited especially for radiopharmaceuticals. This comparative study investigated the discrepancies between predicted and experimental pK a values and their impact on CNS activity prediction scores. The pK a values of 46 substances, including therapeutic drugs and PET imaging radiopharmaceuticals, were measured by means of potentiometry and spectrophotometry. Experimentally obtained pK a values were compared with in silico predictions (Chemicalize/Marvin). The results demonstrate a considerable discrepancy between experimental and in silico values, with linear regression analysis showing intermediate correlation (R 2 (Marvin)  = 0.88, R 2 (Chemicalize)  = 0.82). This indicates that if one requires an accurate pK a value, it is essential to experimentally assess it. This underscores the importance of experimentally determining pK a values for accurate drug design and optimization. The study's data provide a valuable library of reliable experimental pK a values for therapeutic drugs and radiopharmaceuticals, aiding researchers in the field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/Objectives: Cancer-associated cachexia in head and neck squamous cell carcinoma (HNSCC) is challenging to diagnose due to its complex pathophysiology. This study aimed to identify metabolic biomarkers linked to cachexia and survival in HNSCC patients using [ 18 F]FDG-PET/CT imaging and machine learning (ML) techniques. Methods: We retrospectively analyzed 253 HNSCC patients from Vienna General Hospital and the MD Anderson Cancer Center. Automated organ segmentation was employed to quantify metabolic and volumetric data from [ 18 F]FDG-PET/CT scans across 29 tissues and organs. Patients were categorized into low weight loss (LoWL; grades 0-2) and high weight loss (HiWL; grades 3-4) groups, according to the weight loss grading system (WLGS). Machine learning models, combined with Cox regression, were used to identify survival predictors. Shapley additive explanation (SHAP) analysis was conducted to determine the significance of individual features. Results: The HiWL group exhibited increased glucose metabolism in skeletal muscle and adipose tissue ( p = 0.01), while the LoWL group showed higher lung metabolism. The one-year survival rate was 84.1% in the LoWL group compared to 69.2% in the HiWL group ( p < 0.01). Pancreatic volume emerged as a key biomarker associated with cachexia, with the ML model achieving an AUC of 0.79 (95% CI: 0.77-0.80) and an accuracy of 0.82 (95% CI: 0.81-0.83). Multivariate Cox regression confirmed pancreatic volume as an independent prognostic factor (HR: 0.66, 95% CI: 0.46-0.95; p < 0.05). Conclusions: The integration of metabolic and volumetric data provided a strong predictive model, highlighting pancreatic volume as a key imaging biomarker in the metabolic assessment of cachexia in HNSCC. This finding enhances our understanding and may improve prognostic evaluations and therapeutic strategies.

Purpose: Positron emission tomography (PET) provides precise molecular information on physiological processes, but its low temporal resolution is a major obstacle. Consequently, we characterized the metabolic response of the human brain to working memory performance using an optimized functional PET (fPET) framework at a temporal resolution of 3 s., Methods: Thirty-five healthy volunteers underwent fPET with [ 18 F]FDG bolus plus constant infusion, 19 of those at a hybrid PET/MRI scanner. During the scan, an n-back working memory paradigm was completed. fPET data were reconstructed to 3 s temporal resolution and processed with a novel sliding window filter to increase signal to noise ratio. BOLD fMRI signals were acquired at 2 s., Results: Consistent with simulated kinetic modeling, we observed a constant increase in the [ 18 F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. These task-specific changes were robustly observed in brain regions involved in working memory processing. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to individual behavioral performance during working memory. Furthermore, task-induced BOLD deactivations in the posteromedial default mode network were accompanied by distinct temporal patterns in glucose metabolism, which were dependent on the metabolic demands of the corresponding task-positive networks., Conclusions: In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing. This allows to capture unique information in the temporal domain, which is not accessible to conventional PET imaging., (© 2023. The Author(s).)

A substantial portion of patients do not benefit from programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) checkpoint inhibition therapies, necessitating a deeper understanding of predictive biomarkers. Immunohistochemistry (IHC) has played a pivotal role in assessing PD-L1 expression, but small-molecule positron emission tomography (PET) tracers could offer a promising avenue to address IHC-associated limitations, i.e., invasiveness and PD-L1 expression heterogeneity. PET tracers would allow for improved quantification of PD-L1 through noninvasive whole-body imaging, thereby enhancing patient stratification. Here, a large series of PD-L1 targeting small molecules were synthesized, leveraging advantageous substructures to achieve exceptionally low nanomolar affinities. Compound 5c emerged as a promising candidate (IC 50 = 10.2 nM) and underwent successful carbon-11 radiolabeling. However, a lack of in vivo tracer uptake in xenografts and notable accumulation in excretory organs was observed, underscoring the challenges encountered in small-molecule PD-L1 PET tracer development. The findings, including structure-activity relationships and in vivo biodistribution data, stand to illuminate the path forward for refining small-molecule PD-L1 PET tracers.

Functional imaging with prostate-specific membrane antigen (PSMA) ligands has emerged as the standard imaging method for prostate cancer (PCA). In parallel, the analysis of blood-derived, cell-free DNA (cfDNA) has been shown to be a promising quantitative biomarker of PCA aggressiveness and patient outcome. This study aimed to evaluate the relationship and prognostic value of cfDNA concentrations and the PSMA-positive tumor volume (PSMA-TV) in men with PCA undergoing [ 68 Ga]Ga-PSMA-11 PET/CT imaging. Methods: We recruited 148 men with histologically proven PCA (mean age, 70.7 ± 7.7 y) who underwent [ 68 Ga]Ga-PSMA-11 PET/CT (184.9 ± 18.9 MBq) and blood sampling between March 2019 and August 2021. Among these, 74 (50.0%) had hormone-sensitive PCA and 74 (50.0%) had castration-resistant PCA (CRPC). All patients provided written informed consent before blood sample collection and imaging. The cfDNA was extracted and quantified, and PSMA-expressing tumor lesions were delineated to extract the PSMA-TVs. The Spearman coefficient assessed correlations between PSMA-TV and cfDNA concentrations and cfDNA's relation with clinical parameters. The Kruskal-Wallis test examined the mean cfDNA concentration differences based on PSMA-TV quartiles for significantly correlated patient groups. Log-rank and multivariate Cox regression analyses evaluated the prognostic significance of high and low cfDNA and PSMA-TV levels for overall survival. Results: Weak positive correlations were found between cfDNA concentration and PSMA-TV in the overall group ( r = 0.16, P = 0.049) and the CRPC group ( r = 0.31, P = 0.007) but not in hormone-sensitive PCA patients ( r = -0.024, P = 0.837). In the CRPC cohort, cfDNA concentrations significantly differed between PSMA-TV quartiles 4 and 1 ( P = 0.002) and between quartiles 4 and 2 ( P = 0.016). Survival outcomes were associated with PSMA-TV ( P < 0.0001, P = 0.004) but not cfDNA ( P = 0.174, P = 0.12), as per the log-rank and Cox regression analysis. Conclusion: These findings suggest that cfDNA might serve as a biomarker of advanced, aggressive CRPC but does not reliably reflect total tumor burden or prognosis. In comparison, [ 68 Ga]Ga-PSMA-11 PET/CT provides a highly granular and prognostic assessment of tumor burden across the spectrum of PCA disease progression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Studies indicate that the radiotracer 2-[ 18 F]fluoro-2-deoxy-D-glucose (2-[ 18 F]FDG) can be metabolized beyond 2-[ 18 F]FDG-6-phosphate (2-[ 18 F]FDG-6-P), but its metabolism is incompletely understood. Most importantly, it remains unclear whether downstream metabolism affects tracer accumulation in vivo. Here we present a fingerprint of 2-[ 18 F]FDG radiometabolites over time in cancer cells, corresponding tumor xenografts and murine organs. Strikingly, radiometabolites representing glycogen metabolism or the oxPPP correlated inversely with tracer accumulation across all examined tissues. Recent studies suggest that not only hexokinase, but also hexose-6-phosphate dehydrogenase (H6PD), an enzyme of the oxidative pentose phosphate pathway (oxPPP), determines 2-[ 18 F]FDG accumulation. However, little is known about the corresponding enzyme glucose-6-phosphate dehydrogenase (G6PD). Our mechanistic in vitro experiments on the role of the oxPPP propose that 2-[ 18 F]FDG can be metabolized via both G6PD and H6PD, but data from separate enzyme knockdown suggest diverging roles in downstream tracer metabolism. Overall, we propose that tissue-specific metabolism beyond 2-[ 18 F]FDG-6-P could matter for imaging., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Myocardial glycosphingolipid accumulation in patients with Fabry disease (FD) causes biochemical and structural changes. This study aimed to investigate sympathetic innervation in FD using hybrid cardiac positron emission tomography (PET)/magnetic resonance imaging (MRI)., Methods and Results: Patients with different stages of Fabry disease were prospectively enrolled to undergo routine CMR at 1.5T, followed by 3T hybrid cardiac PET/MRI with [ 11 C]meta-hydroxyephedrine ([11C]mHED). Fourteen patients with either no evidence of cardiac involvement (n = 5), evidence of left ventricular hypertrophy (LVH) (n = 3), or evidence of LVH and fibrosis via late gadolinium enhancement (LGE) (n = 6) were analyzed. Compared to patients without LVH, patients with LVH or LVH and LGE had lower median T1 relaxation times (ms) at 1.5 T (1007 vs. 889 vs. 941 ms, p = 0.003) and 3T (1290 vs. 1172 vs. 1184 p = .014). Myocardial denervation ([11C]mHED retention < 7%·min) was prevalent only in patients with fibrosis, where a total of 16 denervated segments was found in two patients. The respective area of denervation exceeded the area of LGE in both patients (24% vs. 36% and 4% vs. 32%). However, sympathetic innervation defects ([11C]mHED retention ≤ 9%·min) occurred in all study groups. Furthermore, a reduced sympathetic innervation correlated with an increased left ventricular mass (p = .034, rs = - 0.57) and a reduced global longitudinal strain (GLS) (p = 0.023, rs = - 0.6)., Conclusion: Hybrid cardiac PET/MR with [11C]mHED revealed sympathetic innervation defects, accompanied by impaired GLS, in early stages of Fabry disease. However, denervation is only present in patients with advanced stages of FD showing fibrosis on CMR., (© 2023. The Author(s).)

PD-1/PD-L1 immune checkpoint blockade for cancer therapy showed promising results in clinical studies. Further endeavors are required to enhance patient stratification, as, at present, only a small portion of patients with PD-L1-positive tumors (as determined by PD-L1 targeted immunohistochemistry; IHC) benefit from anti-PD-1/PD-L1 immunotherapy. This can be explained by the heterogeneity of tumor lesions and the intrinsic limitation of multiple biopsies. Consequently, non-invasive in vivo quantification of PD-L1 on tumors and metastases throughout the entire body using positron emission tomography (PET) imaging holds the potential to augment patient stratification. Within the scope of this work, six new small molecules were synthesized by following a ligand-based drug design approach supported by computational docking utilizing lead structures based on the (2-methyl-[1,1'-biphenyl]-3-yl)methanol scaffold and evaluated in vitro for potential future use as PD-L1 PET tracers. The results demonstrated binding affinities in the nanomolar to micromolar range for lead structures and newly prepared molecules, respectively. Carbon-11 labeling was successfully and selectively established and optimized with very good radiochemical conversions of up to 57%. The obtained insights into the significance of polar intermolecular interactions, along with the successful radiosyntheses, could contribute substantially to the future development of small-molecule PD-L1 PET tracers.

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (V T ) using [ 11 C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A V T as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A V T after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583., (© 2023. The Author(s).)

The nervous and circulatory system interconnects the various organs of the human body, building hierarchically organized subsystems, enabling fine-tuned, metabolically expensive brain-body and inter-organ crosstalk to appropriately adapt to internal and external demands. A deviation or failure in the function of a single organ or subsystem could trigger unforeseen biases or dysfunctions of the entire network, leading to maladaptive physiological or psychological responses. Therefore, quantifying these networks in healthy individuals and patients may help further our understanding of complex disorders involving body-brain crosstalk. Here we present a generalized framework to automatically estimate metabolic inter-organ connectivity utilizing whole-body functional positron emission tomography (fPET). The developed framework was applied to 16 healthy subjects (mean age ± SD, 25 ± 6 years; 13 female) that underwent one dynamic 18 F-FDG PET/CT scan. Multiple procedures of organ segmentation (manual, automatic, circular volumes) and connectivity estimation (polynomial fitting, spatiotemporal filtering, covariance matrices) were compared to provide an optimized thorough overview of the workflow. The proposed approach was able to estimate the metabolic connectivity patterns within brain regions and organs as well as their interactions. Automated organ delineation, but not simplified circular volumes, showed high agreement with manual delineation. Polynomial fitting yielded similar connectivity as spatiotemporal filtering at the individual subject level. Furthermore, connectivity measures and group-level covariance matrices did not match. The strongest brain-body connectivity was observed for the liver and kidneys. The proposed framework offers novel opportunities towards analyzing metabolic function from a systemic, hierarchical perspective in a multitude of physiological pathological states., Competing Interests: Declaration of Competing Interest M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, and Siemens Healthineers. R. Lanzenberger received travel grants and/or conference speaker honoraria from Bruker BioSpin within the last three years and investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. Ivo Rausch received a research grant from Siemens Healthineers not related to this study. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Dynamic positron emission tomography (PET) and the application of kinetic models can provide important quantitative information based on its temporal information. This however requires arterial blood sampling, which can be challenging to acquire. Nowadays, state-of-the-art PET/CT systems offer fully automated, whole-body (WB) kinetic modelling protocols using image-derived input functions (IDIF) to replace arterial blood sampling. Here, we compared the validity of an automatic WB kinetic model protocol to the reference standard arterial input function (AIF) for both clinical and research settings. Methods: Sixteen healthy participants underwent dynamic WB [ 18 F]FDG scans using a continuous bed motion PET/CT system with simultaneous arterial blood sampling. Multiple processing pipelines that included automatic and manually generated IDIFs derived from the aorta and left ventricle, with and without motion correction were compared to the AIF. Subsequently generated quantitative images of glucose metabolism were compared to evaluate performance of the different input functions. Results: We observed moderate to high correlations between IDIFs and the AIF regarding area under the curve (r = 0.49-0.89) as well as for the cerebral metabolic rate of glucose (CMRGlu) (r = 0.68-0.95). Manual placing of IDIFs and motion correction further improved their similarity to the AIF. Discussion: In general, the automatic vendor protocol is a feasible approach for the quantification of CMRGlu for both, clinical and research settings where expertise or time is not available. However, we advise on a rigorous inspection of the placement of the volume of interest, the resulting IDIF, and the quantitative values to ensure valid interpretations. In protocols requiring longer scan times or where cohorts are prone to involuntary movement, manual IDIF definition with additional motion correction is recommended, as this has greater accuracy and reliability., Competing Interests: RL received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. MH received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, and Siemens Healthineers. IR received a research grant from Siemens Healthineers not related to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor CC declared a past co-authorship with the authors TB and IR., (Copyright © 2023 Reed, Godbersen, Vraka, Rausch, Ponce de León, Popper, Geist, Nics, Komorowski, Karanikas, Beyer, Traub-Weidinger, Hahn, Langsteger, Hacker and Lanzenberger.)

Background: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood., Methods: Here, the influence of MAOA promoter/exon I/intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females)., Results: No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr = .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT., Conclusions: In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5' on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system., Clinicaltrials.gov Identifier: NCT02582398 (https://clinicaltrials.gov/ct2/show/NCT02582398)., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT 1A ) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl- 11 C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (V S ) of 5-HT 1A receptor. While post-hoc comparisons showed no significant changes of 5-HT 1A receptor V S in either group, higher 5-HT 1A receptor V S after treatment correlated with greater difference in HAMD (r = -0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT 1A receptor. Due to the small sample size, all results must, however, be regarded with caution., (© 2023. The Author(s).)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [ 11 C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers (n = 26, MAF = 0.18) compared to major allele homozygotes (t 73  = 2.73, p FWE  < 0.05) as well as in men compared to women (t 73  = 3.33, p FWE  < 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was -14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, -4.83 ± 2.70% lower per 10 kg bodyweight, and -2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry., (© 2022. The Author(s).)

Objective: [ 177 Lu]Lu-PSMA radioligand therapy (PSMA-RLT) is a promising therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) and offers a survival benefit particularly to patients with only lymph node metastases. We therefore sought to evaluate the clinical outcome of this therapy in such a cohort., Methods: Of all prostate cancer patients admitted to our department between September 2015 and March 2019 to receive 1-4 courses of PSMA-RLT (each course consisted of three cycles of highly standardized PSMA-RLT every 4 weeks), only 10 consecutive men were found to have nodal metastases only and were analyzed retrospectively., Results: Nine out of 10 patients responded to their first PSMA-RLT course with a mean prostate-specific antigen (PSA) decline of 71.8 ± 25.2%, seven of them demonstrated a PSA decline of ≥50%. Collectively, seven of eight patients responded to further PSMA-RLT courses with a total PSA reduction of 59.8 ± 30.0%, five of which showed a PSA reduction of ≥50%. One patient experienced complete remission. Median progression-free survival was 85 weeks (range 14-255 weeks) and median overall survival was not reached during the median observation time of 209 weeks (30-298 weeks). Univariate Cox-regression identified initial PSA decline as the only predictive parameter for progression-free survival ( P = 0.047)., Conclusion: mCRPC patients with only lymph node metastases showed favorable survival and excellent response to PSMA-RLT, leading to transient partial remission of the disease in most of them., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission. While synaptic NMDARs are thought to have protective characteristics, activation of extrasynaptic NMDARs might trigger excitotoxic processes linked to neuropsychiatric disorders. Since extrasynaptic NMDARs are typically GluN2B-enriched, the subunit is an interesting target for drug development and treatment monitoring. Recently, the novel GluN2B-specific PET radioligand (R)-[ 11 C]Me-NB1 was investigated in rodents and for the first time successfully translated to humans. To assess whether (R)-[ 11 C]Me-NB1 is a valuable radioligand for (repeated) clinical applications, we evaluated its safety, biodistribution and dosimetry., Methods: Four healthy subjects (two females, two males) underwent one whole-body PET/MR measurement lasting for more than 120 min. The GluN2B-specific radioligand (R)-[ 11 C]Me-NB1 was administered simultaneously with the PET start. Subjects were measured in nine passes and six bed positions from head to mid-thigh. Regions of interest was anatomically defined for the brain, thyroid, lungs, heart wall, spleen, stomach contents, pancreas, liver, kidneys, bone marrow and urinary bladder contents, using both PET and MR images. Time-integrated activity coefficients were estimated to calculate organ equivalent dose coefficients and the effective dose coefficient. Additionally, standardized uptake values (SUV) were computed to visualize the biodistribution., Results: Administration of the radioligand was safe without adverse events. The organs with the highest uptake were the urinary bladder, spleen and pancreas. Organ equivalent dose coefficients were higher in female in almost all organs, except for the urinary bladder of male. The effective dose coefficient was 6.0 µSv/MBq., Conclusion: The GluN2B-specific radioligand (R)-[ 11 C]Me-NB1 was well-tolerated without reported side effects. Effective dose was estimated to 1.8 mSv when using 300 MBq of presented radioligand. The critical organ was the urinary bladder. Due to the low effective dose coefficient of this radioligand, longitudinal studies for drug development and treatment monitoring of neuropsychiatric disorders including neurodegenerative diseases are possible. Trial registration Registered on 11th of June 2019 at https://www.basg.gv.at (EudraCT: 2018-002933-39)., (© 2022. The Author(s).)

Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague-Dawley rats, and in vivo cardiac 2-[ 18 F]FDG and [ 11 C]mHED PET scans were performed at 14-15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[ 18 F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats (P > 0.05). However, the mean [ 11 C]mHED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism., (© 2022. The Author(s).)

The N -methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, ( R )- 11 C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this radioligand in a first-in-humans PET study. Methods: Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with ( R )- 11 C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by SUVs. Test-retest reliability was assessed with the absolute percentage difference and the coefficient of variation. Exploratory total volumes of distribution (V T ) were computed using an arterial input function and the Logan plot as well as a constrained 2-tissue-compartment model with the ratio of rate constants between plasma and tissue compartments ( K 1 / k 2 ) coupled (2TCM). SUV was correlated with V T to investigate its potential as a surrogate marker of GluN2B expression. Results: High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV absolute percentage difference ranged from 6.9% to 8.5% and coefficient of variation from 4.9% to 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70 to 90 min and V T using Logan plot (Spearman ρ = 0.44). Correlation between V T Logan and 2TCM was r = 0.76. Conclusion: C-Me-NB1 was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.R )- 11 C-Me-NB1 was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Simultaneous characterization of pathologies by multi-tracer positron emission tomography (PET) is among the most promising applications in nuclear medicine. Aim of this work was the simultaneous production of two PET-tracers in one module and test the relevance for human application. [ 11 C]harmine and [ 11 C]DASB were concurrently synthesized in a 'two-in-one-pot' reaction in quality for application. Dual-tracer protocol was simulated using 16 single PET scans in different orders of tracer application separated by different time intervals. Volume of distribution was calculated for single- and dual-tracer measurements using Logan's plot and arterial input function in 13 brain regions. The 'two-in-one-pot' reaction yielded equivalent amounts of both radiotracers with comparable molar activities. The simulations of the dual-tracer application were comparable to the single bolus injections in 13 brain regions, when [ 11 C]harmine was applied first and [ 11 C]DASB second, with an injection time interval of 45 min (r xy  = 0.90). Our study shows the successful simultaneous dual-tracer production leading to decreased radiation burden and costs. The simulation of dual subject injection to quantify the monoamine oxidase-A and serotonin transporter distribution proved its high potential. Multi-tracer imaging may drive more sophisticated study designs and diminish the day-to-day differences in the same individual as well as increase PET scanner efficiency., (© 2022. The Author(s).)

Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results., (© 2021. The Author(s).)

The sex hormones testosterone and estradiol influence brain structure and function and are implicated in the pathogenesis, prevalence and disease course of major depression. Recent research employing gender-affirming hormone treatment (GHT) of gender dysphoric individuals and utilizing positron emission tomography (PET) indicates increased serotonin transporter binding upon high-dosages of testosterone treatment. Here, we investigated the effects of GHT on levels of monoamine oxidase A (MAO-A), another key target of antidepressant treatment. Participants underwent PET with the radioligand [ 11 C]harmine to assess cerebral MAO-A distribution volumes (V T ) before and four months after initiation of GHT. By the time this study was terminated for technical reasons, 18 transgender individuals undergoing GHT (11 transmen, TM and 7 transwomen, TW) and 17 cis-gender subjects had been assessed. Preliminary analysis of available data revealed statistically significant MAO-A V T reductions in TM under testosterone treatment in six of twelve a priori defined regions of interest (middle frontal cortex (-10%), anterior cingulate cortex (-9%), medial cingulate cortex (-10.5%), insula (-8%), amygdala (-9%) and hippocampus (-8.5%, all p<0.05)). MAO-A V T did not change in TW receiving estrogen treatment. Despite the limited sample size, pronounced MAO-A V T reduction could be observed, pointing towards a potential effect of testosterone. Considering MAO-A's central role in regulation of serotonergic neurotransmission, changes to MAO-A V T should be further investigated as a possible mechanism by which testosterone mediates risk for, symptomatology of, and treatment response in affective disorders., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: [ 177 Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) could affect kidney and salivary gland functions in metastatic castration-resistant prostate cancer (mCRPC) patients., Methods: We retrospectively analyzed clinical, renal, and salivary scintigraphy data and salivary [ 68 Ga]Ga-PSMA-11 ligand PET scan measures such as metabolic volume and SUVmax values of 27 mCRPC men (mean age 71 ± 7 years) before and 4 weeks after receiving three cycles of PSMA-RLT every 4 weeks. Twenty-two patients additionally obtained renal and salivary scintigraphy prior to each cycle. A one-way ANOVA, post-hoc Scheffé test and Cochran's Q test were applied to assess organ toxicity., Results: In total, 54 PSMA PET scans, 98 kidney, and 98 salivary scintigraphy results were evaluated. There were no significant differences for the ejection fraction, peak time, and residual activity after 5 min for both parotid and submandibular glands prior to each cycle and 4 weeks after the last cycle. Similarly, no significant differences in serum creatinine and renal scintigraphy parameters were observed prior to each cycle and 4 weeks after the last treatment. Despite there being no changes in the metabolic volume of both submandibular glands, SUVmax values dropped significantly ( p < 0.05)., Conclusion: Results evidenced no alterations in renal function and only minimal impairment of salivary function of mCRPC patients who acquired an intense PSMA-RLT regimen every 4 weeks.

The glucose derivative 2-[ 18 F]fluoro-2-deoxy-D-glucose (2-[ 18 F]FDG) is still the most used radiotracer for positron emission tomography, as it visualizes glucose utilization and energy demand. In general, 2-[ 18 F]FDG is said to be trapped intracellularly as 2-[ 18 F]FDG-6-phosphate, which cannot be further metabolized. However, increasingly, this dogma is being questioned because of publications showing metabolism beyond 2-[ 18 F]FDG-6-phosphate and even postulating 2-[ 18 F]FDG imaging to depend on the enzyme hexose-6-phosphate dehydrogenase in the endoplasmic reticulum. Therefore, we aimed to study 2-[ 18 F]FDG metabolism in the human cancer cell lines HT1080, HT29 and Huh7 applying HPLC. We then compared 2-[ 18 F]FDG metabolism with intracellular tracer accumulation, efflux and the cells' metabolic state and used a graphical Gaussian model to visualize metabolic patterns. The extent of 2-[ 18 F]FDG metabolism varied considerably, dependent on the cell line, and was significantly enhanced by glucose withdrawal. However, the metabolic pattern was quite conserved. The most important radiometabolites beyond 2-[ 18 F]FDG-6-phosphate were 2-[ 18 F]FDMannose-6-phosphate, 2-[ 18 F]FDG-1,6-bisphosphate and 2-[ 18 F]FD-phosphogluconolactone. Enhanced radiometabolite formation under glucose reduction was accompanied by reduced efflux and mirrored the cells' metabolic switch as assessed via extracellular lactate levels. We conclude that there can be considerable metabolism beyond 2-[ 18 F]FDG-6-phosphate in cancer cell lines and a comprehensive understanding of 2-[ 18 F]FDG metabolism might help to improve cancer research and tumor diagnosis.

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via β-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [ 18 F]FDG and the MCHR1-tracer [ 11 C]SNAP-7941. We found that the β3-adrenoceptor (ADRB3) agonist CL316,243 increased [ 11 C]SNAP-7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941-a low-affinity ADRB3 ligand-stimulated [ 18 F]FDG uptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 induced MCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link between MCHR1 and the β3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity., (© 2021 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [ 177 Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients., Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87-1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan-Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival., Results: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6-1926 µg/L, p = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer ( p = 0.02), whereas the patients with bone metastases had a shorter survival ( p = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS ( p < 0.05, hazard ratio 2.43, 95% CI 1.01-5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, p = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, p = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded., Conclusion: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS.

Background and Aims: [ 177 Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks., Patients and Methods: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS)., Results: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT., Conclusion: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.

Background/aim: Positron emission tomography/computed tomography (PET/CT) plays an important role in cancer localization in ectopic Cushing's syndrome (ECS). However, the choice of the optimal tracer for investigation of this disease is still unclear. We aimed to evaluate the diagnostic feasibility of [ 18 F]fluoro-2-deoxyglucose ([ 18 F]FDG), [ 18 F]fluoro-L-dihydroxyphenylalanine ([ 18 F] FDOPA), and [ 68 Ga]-DOTA-1-Nal3-octreotide ([ 68 Ga]-DOTANOC) in ECS., Patients and Methods: All PET/CT scans of patients admitted to our department for suspected ECS between 2010 and 2020 were retrospectively analysed., Results: Collectively, 30 PET/CT examinations, 11 with [ 18 F]FDOPA, 11 with [ 18 F]FDG and 8 with [ 68 Ga]GaDOTANOC were conducted for 18 patients eligible for analysis. [ 18 F]FDG detected the tumour in 3/6 of the cases, [ 18 F]FDOPA in 3/4, and [ 68 Ga]GaDOTANOC in 3/3. [ 18 F]FDOPA was the only tracer without false positive results., Conclusion: [ 68 Ga]GaDOTANOC and [ 18 F]FDOPA showed superior results compared to [ 18 F]FDG, although the sensitivity of the tracers might be influenced by the aetiology of the tumour underlying the ECS., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

99m Tc-PHC-102 is a 99m Tc-labeled derivative of acetazolamide, a high-affinity small organic ligand of carbonic anhydrase IX (CAIX). 99m Tc-PHC-102 has previously shown favorable in vivo biodistribution properties in mouse models of CAIX-positive clear cell renal cell carcinoma (ccRCC) and colorectal cancer. In this study, we aimed to explore the targeting performance of 99m Tc-PHC-102 in SPECT in patients with renal cell carcinoma while also assessing the safety and tolerability of the radiotracer. Methods: We studied 5 patients with localized or metastatic ccRCC in a microdosing regimen, after the administration of a 50-μg total of CAIX ligand and 600-800 MBq of 99m Tc-PHC-102. Tissue distribution and residence time in normal organs and tumors were analyzed by serial SPECT/CT scans at 3 time points (30 min, 2 h, and 6 h) after intravenous administration. Results: In the 5 patients studied, 99m Tc-PHC-102 was well tolerated and no study drug-related adverse events were recorded. In the stomach, kidneys, and gallbladder, the radiotracer showed a rapid initial uptake, which cleared over time. Localization of the study drug in primary tumors of 5 patients was observed, with favorable tumor-to-background ratios. 99m Tc-PHC-102 SPECT/CT allowed the identification of 4 previously unknown lung and lymph node metastases in 2 patients. Conclusion: 99m Tc-PHC-102 is a promising SPECT tracer for the imaging of patients with ccRCC. This tracer has the potential to identify primary and metastatic lesions in different anatomic locations. 99m Tc-PHC-102 might also serve as a companion diagnostic agent for future CAIX-targeting therapeutics., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)