Dynamics of human serotonin synthesis differentially link to reward anticipation and feedback.

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 [11C]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.

Amphetamine-Induced Dopamine Release Predicts 1-Year Outcome in First-Episode Psychosis: A Naturalistic Observation.

BACKGROUND AND HYPOTHESIS: The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d-amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia. STUDY DESIGN: Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d-amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29). STUDY RESULTS: A group analysis revealed no significant differences in d-amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d-amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r = 0.54, P = .04; uncorrected P-values); release in globus pallidus correlated with a decrease in PANSS negative (r = 0.58, P = .02), general (r = 0.53, P = .04), and total symptom scores (r = 0.063, P = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r = 0.51, P = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r = 0.66, P = .005) and throughout all follow-up visits. CONCLUSIONS: These exploratory results support a relationship between d-amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis.

First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues.

PURPOSE: Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. METHODS: Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h- 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology. RESULTS: Mean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h- 1 (- 4 ± 24%), cerebellum: 0.033 ± 0.009 h- 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h- 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h- 1 (30 ± 38%), lungs: 0.875 ± 0.095 h- 1 (- 3 ± 11%), myocardium: 0.641 ± 0.105 h- 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h- 1 (14 ± 16%), and liver: 0.685 ± 0.072 h- 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women. CONCLUSION: LAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans. TRIAL REGISTRATION: EudraCT 2021-006348-29. Registered 15 December 2021.

In vivo assessment of safety, biodistribution, and radiation dosimetry of the [18F]Me4FDG PET-radiotracer in adults.

BACKGROUND: Approaches targeting the sodium-glucose cotransporter (SGLT) could represent a promising future therapeutic strategy for numerous oncological and metabolic diseases. In this study, we evaluated the safety, biodistribution and radiation dosimetry of the glucose analogue positron emission tomography (PET) agent [18F] labeled alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) with high sodium-glucose cotransporter and low glucose transporter (GLUT) affinity. For this purpose, five healthy volunteers (1 man, 4 women) underwent multiple whole-body PET/computed tomography (CT) examinations starting with injection and up to 4 h after injection of averaged (2.4 ± 0.1) MBq/kg (range: 2.3-2.5 MBq/kg) administered activity. The PET/CT scans were conducted in 5 separate sessions, blood pressure and temperature were measured, and blood and urine samples were collected before the scans and one hour after injection to assess toxicity. Measurements of [18F]Me4FDG radioactivity in organs of interest were determined from the PET/CT scans at 5 time points. Internal dosimetry was performed on voxel level using a fast Monte Carlo approach. RESULTS: All studied volunteers could well tolerate the [18F]Me4FDG and no adverse event was reported. The calculated effective dose was (0.013 ± 0.003) mSv/MBq. The organs with the highest absorbed dose were the kidneys with 0.05 mSv/MBq per kidney. The brain showed almost no uptake. After 60 min, (12 ± 15) % of the administered dose was excreted into the bladder. CONCLUSION: Featuring an effective dose of only 0.013 ± 0.003 mSv/MBq and no occurrence of side effects, the glucose analogue [18F]Me4FDG seems to be a safe radio-tracer with a favorable biodistribution for PET imaging and also within several consecutive scans. TRIAL REGISTRATION NUMBER: NCT03557138, Registered 22 February 2017, https://ichgcp.net/clinical-trials-registry/NCT03557138 .

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Assessment of PSMA Expression of Healthy Organs in Different Stages of Prostate Cancer Using [68Ga]Ga-PSMA-11-PET Examinations.

The efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is currently being investigated for its application in patients with early-stage prostate cancer (PCa). However, little is known about PSMA expression in healthy organs in this cohort. Collectively, 202 [68Ga]Ga-PSMA-11 positron emission tomography (PET) scans from 152 patients were studied. Of these, 102 PET scans were from patients with primary PCa and hormone-sensitive biochemically recurrent PCa and 50 PET scans were from patients with metastatic castration-resistant PCa (mCRPC) before and after three cycles of [177Lu]Lu-PSMA-RLT. PSMA-standardized uptake values (SUV) were measured in multiple organs and PSMA-total tumor volume (PSMA-TTV) was determined in all cohorts. The measured PET parameters of the different cohorts were normalized to the bloodpool and compared using t- or Mann-Whitney U tests. Patients with early-stage PCa had lower PSMA-TTVs (10.39 mL vs. 462.42 mL, p < 0.001) and showed different SUVs in the thyroid, submandibular glands, heart, liver, kidneys, intestine, testes and bone marrow compared to patients with advanced CRPC, with all tests showing p < 0.05. Despite the differences in the PSMA-TTV of patients with mCRPC before and after [177Lu]Lu-PSMA-RLT (462.42 mL vs. 276.29 mL, p = 0.023), no significant organ differences in PET parameters were detected. These suggest different degrees of PSMA-ligand binding among patients with different stages of PCa that could influence radiotoxicity during earlier stages of disease in different organs when PSMA-RLT is administered.

Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates.

BACKGROUND: 6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. RESULTS: [11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/µmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. CONCLUSIONS: [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

Validation of cardiac image-derived input functions for functional PET quantification.

PURPOSE: Functional PET (fPET) is a novel technique for studying dynamic changes in brain metabolism and neurotransmitter signaling. Accurate quantification of fPET relies on measuring the arterial input function (AIF), traditionally achieved through invasive arterial blood sampling. While non-invasive image-derived input functions (IDIF) offer an alternative, they suffer from limited spatial resolution and field of view. To overcome these issues, we developed and validated a scan protocol for brain fPET utilizing cardiac IDIF, aiming to mitigate known IDIF limitations. METHODS: Twenty healthy individuals underwent fPET/MR scans using [18F]FDG or 6-[18F]FDOPA, utilizing bed motion shuttling to capture cardiac IDIF and brain task-induced changes. Arterial and venous blood sampling was used to validate IDIFs. Participants performed a monetary incentive delay task. IDIFs from various blood pools and composites estimated from a linear fit over all IDIF blood pools (3VOI) and further supplemented with venous blood samples (3VOIVB) were compared to the AIF. Quantitative task-specific images from both tracers were compared to assess the performance of each input function to the gold standard. RESULTS: For both radiotracer cohorts, moderate to high agreement (r: 0.60-0.89) between IDIFs and AIF for both radiotracer cohorts was observed, with further improvement (r: 0.87-0.93) for composite IDIFs (3VOI and 3VOIVB). Both methods showed equivalent quantitative values and high agreement (r: 0.975-0.998) with AIF-derived measurements. CONCLUSION: Our proposed protocol enables accurate non-invasive estimation of the input function with full quantification of task-specific changes, addressing the limitations of IDIF for brain imaging by sampling larger blood pools over the thorax. These advancements increase applicability to any PET scanner and clinical research setting by reducing experimental complexity and increasing patient comfort.

Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET.

PURPOSE: Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. METHODS: We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. RESULTS: We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. CONCLUSION: The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.

A Fully Automated Synthesis of 14-(R,S)-[18F]fluoro-6-thia-heptadecanoic Acid ([18F]FTHA) on the Elixys Radiosynthesizer.

14-(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA) is a radiocompound for imaging the fatty acid circulation by positron emission tomography. A revived interest in imaging of lipid metabolism led us to a constant tracer production over three years, initially using a conventional vessel-based synthesizer and later transitioning to the cassette-based Elixys synthesizer. On the Elixys module, the radiochemical yield of [18F]FTHA could be increased by more than two times, reaching 13.01 ± 5.63% at the end of the synthesis, while maintaining necessary quality control results.

High-temporal resolution functional PET/MRI reveals coupling between human metabolic and hemodynamic brain response.

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 [18F]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 [18F]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.

Quality Assurance Investigations and Impurity Characterization during Upscaling of [177Lu]Lu-PSMAI&T.

[177Lu]Lu-PSMAI&T is widely used for the radioligand therapy of metastatic castration-resistant prostate cancer (mCRPC). Since this kind of therapy has gained a large momentum in recent years, an upscaled production process yielding multiple patient doses in one batch has been developed. During upscaling, the established production method as well as the HPLC quality control were challenged. A major finding was a correlation between the specific activity and the formation of a pre-peak, presumably caused by radiolysis. Hence, nonradioactive reference standards were irradiated with an X-ray source and the formed pre-peak was subsequently identified as a deiodination product by UPLC-MS. To confirm the occurrence of the same deiodinated side product in the routine batch, a customized deiodinated precursor was radiolabeled and analyzed with the same HPLC setup, revealing an identical retention time to the pre-peak in the formerly synthesized routine batches. Additionally, further cyclization products of [177Lu]Lu-PSMAI&T were identified as major contributors to radiochemical impurities. The comparison of two HPLC methods showed the likelihood of the overestimation of the radiochemical purity during the synthesis of [177Lu]Lu-PSMAI&T. Finally, a prospective cost reduction through an optimization of the production process was shown.

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo.

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 (VT) using [11C]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 VT 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 VT 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.

68Ga-Pentixafor PET/MRI for Treatment Response Assessment in Mantle Cell Lymphoma: Comparison Between Changes in Lesion CXCR4 Expression on PET and Lesion Size and Diffusivity on MRI.

PURPOSE: The aim of this study was to compare CXCR4 imaging with 68Ga-pentixafor PET to MRI for treatment response assessment in patients with mantle cell lymphoma (MCL). PATIENTS AND METHODS: Twenty-two posttreatment 68Ga-pentixafor PET/MRI scans of 16 patients (7 women and 9 men; mean age, 69.9 ± 7.9) with a total of 67 target lesions on baseline PET/MRI were analyzed. Rates of complete remission per lesion and per scan, according to MRI (based on lesion size) and 68Ga-pentixafor PET (based on SUV decrease to lower than liver and blood pool uptake), were compared using McNemar tests. The t tests and Pearson correlation coefficients (r) were used to compare rates of change in lesion diameter products (DPs) on MRI, and standardized uptake values (SUVmax, SUVmean) on PET, relative to baseline. RESULTS: At interim PET/MRI, 18/32 (56.3%) target lesions met CR criteria on 68Ga-pentixafor PET, and 16/32 (50.0%) lesions met size-based MRI criteria for CR (P = 0.63). At end-of-treatment PET/MRI, 40/57 (70.2%) target lesions met 68Ga-pentixafor PET criteria for CR, and 27/57 (47.4%) lesions met size-based MRI criteria for CR (P = 0.021). Complete remission after treatment was observed more frequently on 68Ga-pentixafor PET (11/22 scans, 54.5%) than on MRI (6/22 scans, 27.3%) (P = 0.031). Rates of change did not differ significantly between lesion DP (-69.20% ± 34.62%) and SUVmax (-64.59% ± 50.78%, P = 0.22), or DP and SUVmean (-60.15 ± 64.58, P = 0.064). Correlations were strong between DP and SUVmax (r = 0.71, P < 0.001) and DP and SUVmean (r = 0.73, P < 0.001). CONCLUSIONS: In MCL patients, 68Ga-pentixafor PET may be superior for assessment of complete remission status than anatomic MRI using lesion size criteria, especially at the end of treatment.

Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus.

PURPOSE: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) regulation, developed as treatment for patients with type 2 diabetes, can be imaged with the glucose analogue alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside (Me4FDG), a positron emission tomography (PET) tracer with a high affinity for SGLT1 and SGLT2 proteins. With regard to therapy effectiveness, we aimed to investigate whether clinical parameters or Me4FDG excretion could predict response to SGLT2i in patients with type 2 diabetes. METHODS: In a longitudinal, prospective study, 19 patients with type 2 diabetes underwent Me4FDG combined PET and magnetic resonance imaging (PET/MRI) scans at baseline and 2 weeks after initiation of therapy with SGLT2i, accompanied by the collection of blood and urine samples. Me4FDG-excretion was determined from the Me4FDG uptake in the bladder. Long-term response was determined by HbA1c level after 3 months; a strong response to the therapy was defined as a reduction of HbA1c by at least 10% from baseline. RESULTS: SGLT2i resulted in significantly increased Me4FDG excretion (4.8 vs. 45.0, P < 0.001) and urine glucose (56 vs. 2806 mg/dl, P < 0.001). Baseline urine glucose and baseline Me4FDG excretion correlated both with long-term decline in HbA1c with r = 0.55 (P < 0.05). However, only Me4FDG excretion was a predictor of a strong response to SGLT2i (P = 0.005, OR 1.9). CONCLUSIONS: Using Me4FDG-PET, we demonstrated for the first time renal SGLT2-related excretion before and after short-term SGLT2i treatment. In contrary to other clinical parameters, SGLT2-related excretion before treatment was a robust predictor of long-term HbA1c response in patients with type 2 diabetes, suggesting that therapy effectiveness is only dependent of endogenous SGLT2 processes.

Comparison of cardiac image-derived input functions for quantitative whole body [18F]FDG imaging with arterial blood sampling.

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 [18F]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.

Whole-body metabolic connectivity framework with functional PET.

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 18F-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.

Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease.

Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.

Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors in the dorsolateral prefrontal cortex in treatment-resistant depression: a proof-of-concept trial.

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-HT1A) 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-11C]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 (VS) of 5-HT1A receptor. While post-hoc comparisons showed no significant changes of 5-HT1A receptor VS in either group, higher 5-HT1A receptor VS 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-HT1A receptor. Due to the small sample size, all results must, however, be regarded with caution.

Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.

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).