The prevalence of neurodegenerative diseases (ND), including Alzheimer's disease (AD) and non-AD tauopathies, is projected to rise significantly by 2050 due to an aging global population. Chronic neuroinflammation, driven by glial activation in response to protein pathologies, is a major contributor to disease progression. Targeting glial dysfunction through immunomodulatory therapies offers a promising approach to mitigate the effects of tauopathies and other ND. PS19 mice receive chronic treatment with GV1001 over 5 months. Serial neuroimaging techniques, including PET scans targeting tau protein, microglial activation, and astrocytic responses, are employed to assess treatment effects in vivo (Figure 1). Postmortem validation is performed using immunohistochemistry and biochemical methods, comparing treated mice to placebo and non-transgenic controls. The research scope is to monitor the efficacy of GV1001 in a transgenic tau mouse model (PS19) with an early-intervention biomarker study using molecular biology and neuroimaging techniques including TSPO (microglia) PET, deprenyl (astroglia) PET, tau PET (perfusion and retention) and CSF markers of inflammation (e.g. sTREM2) and neurodegeneration (NfL). Preliminary findings, expected to be presented at the conference, will provide insights into the drug's ability to modulate glial activity, restore homeostasis, and reduce tau pathology. This study highlights the potential of monitoring immunomodulatory strategies to address the complex interplay between chronic neuroinflammation and protein aggregation in ND. If successful, these findings could inform the development of novel therapeutic approaches for AD and related disorders, bridging the gap between preclinical research and clinical application.

In tauopathies, tau accumulation and neuroinflammation are associated with progressive synaptic and network alterations that contribute to neurodegeneration. We used 8 PS19 and 12 C57Bl/6 (WT) mice undergoing consecutive [18F]UCB-H PET scans between 5.7 and 11.0 months of age to longitudinally evaluate SV2A expression levels, with terminal validation via immunohistochemistry. A desynchronization index (DI) quantified deviation from a reference-derived inter-regional SV2A expression pattern from whole-brain SV2A-PET data, and principal component analysis (PCA) further summarized these regional deviation profiles. Baseline translocator protein (TSPO, [18F]GE-180) and monoamine oxidase B (MAO-B, [18F]F-DED) imaging for activated microglia and reactive astrogliosis were performed to detect early neuroinflammation, which was subsequently correlated with serial SV2A expression, evaluated by the area under the curve (AUC) of [18F]UCB-H z-scores (PS19 vs. WT). We observed phased SV2A expression alterations in PS19 mice in the neocortex, hippocampus CA1, brainstem, thalamus, hypothalamus, and cerebellum, showing an increasing trend from 8.4 to 10.0 months of age (+8.1% ± 3.0%), followed by a rapid decline towards 11.0 months of age (-18.4% ± 4.7%), together with greater later-stage inter-regional SV2A expression pattern deviation. Tau burden tended to show a broadly negative association with SV2A expression levels across primary and exploratory regions. Associations of SV2A-PET signal variation with early microglial activation and reactive astrogliosis differed between PS19 and WT mice. In summary, these findings suggest that longitudinal [18F]UCB-H PET may provide a feasible approach for tracking stage-dependent regional SV2A expression alterations and inter-regional deviation in this mouse model of primary tauopathy.

Animal models of acute unilateral vestibulopathy are well established for the study of adaptive lesion-induced neuroplasticity, because symptoms of acute vestibular asymmetry such as nystagmus and postural imbalance recover over time as central vestibular compensation mechanisms commence action. The purpose of this study was to compare these mechanisms in a postganglionic complete unilateral vestibular neurectomy model (UVN) vs. a preganglionic incomplete chemical unilateral labyrinthectomy model (cUL) using a longitudinal [18F]FDG/[18F]UCB-H dual tracer positron emission tomography (PET) approach accompanied by multimodal behavioral testing. Twenty-four male Sprague Dawley rats underwent either cUL or UVN. Postoperatively, [18F]FDG PETs were conducted weekly for four weeks to depict changes of [18F]FDG as a surrogate for functional plasticity, and [18F]UCB-H PETs were carried out at three time points over nine weeks to visualize alterations in synaptic density indicating structural plasticity. Behavioral recovery was assessed weekly using a clinical scoring system and open field evaluation. Behavioral data reflected comparable compensation dynamics between groups. Both [18F]FDG and [18F]UCB-H PET revealed a similar spatial pattern of brain regions involved in adaptive neuroplasticity. However, while the relative extent of [18F]FDG uptake in these networks was comparable across both models, synaptic density changes were more pronounced in UVN vs. cUL. Specifically, synaptic density in the vestibular nuclei was significantly lower after UVN, accompanied by a more intense compensatory increase in sensorimotor cortical areas. In conclusion, synaptic density imaging may be a more sensitive method to depict subtle differences in mechanisms of lesion-induced adaptive neuroplasticity than traditional techniques such as imaging of glucose metabolism.

Validation of threshold-based PET segmentation and PET quantification is typically performed with fillable phantoms. Theoretical considerations show that the inactive walls of the phantom cavities introduce a contrast dependence of the volume-reproducing threshold (VRT), potentially leading to segmentation errors and therefore miscalculations of target volumes. The goal of this study was to experimentally show the contrast independence of the VRT when using wall-less phantoms. Radioactive spheres were produced according to NEMA specifications (D = 10/13/17/22/28/37 mm) using a stereolithographic (SLA) 3D printer. For comparison, hollow spheres were filled with a similar activity concentration. Image data from both sphere types were acquired with five different signal-to-background ratios (SBR = 2/4/6/8/10) using a Siemens mCT 20 and a Biograph 64 TruePoint PET/CT system. Results from wall-less and fillable spheres were compared to evaluate contrast dependence and segmentation accuracy based on VRT and intensity profiles. Wall-less phantoms demonstrated consistent VRT values, with a coefficient of variation of 2

Ziel/Aim: Current clinical dosimetry focuses on activity uptake at millimeter scales, measurable by SPECT or PET imaging. However, understanding the heterogeneous uptake distribution at the cellular level and its effect on dosimetry is essential for assessing response to radionuclide therapy. This study investigated the prolonged uptake kinetics of 177Lu-PSMA-I&T and 177Lu-PSMA-617 in LNCaP cells to determine cellular absorbed doses and correlate them with treatment effects.

Ziel/Aim: [18F]D2-Deprenyl bindet an das Enzym MAO-B und ermöglicht so Rückschlüsse auf die Aktivität von Astrozyten, als Index der Neuroinflammation im ZNS. Bislang wurde [18F]D2-Deprenyl-PET vor allem zur Untersuchung von neurodegenerativen Erkrankungen wie Alzheimer und ALS eingesetzt. Glioblastome sind die häufigsten primären Hirntumore. Da sie von entarteten Astrozyten ausgehen könnte eine Bildgebung durch [18F]D2-Deprenyl-PET auch hier von Nutzen sein, jedoch auch zur Erfassung der Neuroinflammation dienen.

Immune checkpoint inhibition has shown promising results in malignant melanoma, but not all patients respond equally well, necessitating early, accurate monitoring of immunotherapy response. [18F]FDG-PET/CT aids in characterising therapy response beyond morphology, but validated imaging biomarkers for immunotherapy response remain scarce. This study investigated three-time point [18F]FDG-PET/CT to monitor combined anti-PD-L1/anti-CTLA-4 immunotherapy in murine melanoma allografts and compared quantitative in vivo imaging biomarkers with ex vivo biomarkers from multiparametric immunohistochemistry at each time point. Melanoma cells (B16-F10) were injected subcutaneously into C57BL/6 mice (n = 40). Seven days post-inoculation, baseline [18F]FDG-PET/CT was conducted. Animals were randomized into two groups; the therapy group received 5 i.p.-injections of anti-PD-L1/anti-CTLA-4 (20 µg/kg) on days 7, 9, 11, 13 and 15 after tumor cell inoculation. The control group received sham treatment. PET/CT was performed at baseline (day 7 post inoculation), follow-up 1(day 13; FU-1) and follow-up 2 (day 19; FU-2). Tumor allografts were harvested at each time point for immunohistochemistry (CD8, Ki-67, TUNEL) to validate imaging parameters (MTV, SUVmax). At FU-1, the therapy group exhibited significantly lower MTV than the control group (p = 0.004). At FU-2, MTV and SUVmax were significantly lower (MTV: p = 0.008; SUVmax: p = 0.0003) compared to controls. Ex vivo analysis revealed significant anti-tumor effects in the therapy group, with higher apoptosis rates (FU-1: p = 0.012; FU-2: p = 0.001), more CD8-positive T-cells (FU-2: p = 0.003) and lower tumor cell proliferation (FU-1: p = 0.012; FU-2: p = 0.012). Multi-time point [18F]FDG-PET/CT allowed for early non-invasive monitoring of combined anti-PD-L1/anti-CTLA-4 immunotherapy in experimental melanomas, validated by multiparametric immunohistochemistry with significant pro-immunogenic, pro-apoptotic and anti-proliferative effects.

Longitudinal studies on mouse models related to Alzheimer disease (AD) pathology play an important role in the investigation of therapeutic targets to help pharmaceutical research in the development of new drugs and in the attempt of an early diagnosis that can contribute to improving people's quality of life. There are several advantages to enriching longitudinal studies in AD models with Positron Emission Tomography (PET); among these advantages, the possibility of following the principle of the 3Rs of animal welfare is fundamental. In this manuscript, good daily experimental practice focusing on animal welfare is described and commented upon, based on the experience attained from studies conducted in our Nuclear Medicine department.

IntroductionBetahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not effective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test different application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their effects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats.MethodsSixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (1 mg/kg bid), i.v. high-dose betahistine (10 mg/kg bid), p.o. betahistine (1 mg/kg bid)/selegiline (1 mg/kg once daily), s.c. betahistine (continuous release of 4.8 mg/day), and i.v. normal saline bid (sham treatment; days 1–3 post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day 30 post-UL and paralleled by sequential cerebral [18F]-FDG-μPET measurements.ResultsThe therapeutic effects of betahistine after UL differed in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced on 2–3 days post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to 5-fold from 2 to 30 days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [18F]-FDG-μPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day 3 post-UL for i.v. high- vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From 1 to 30 days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment.DiscussionBetahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher effective plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.

IntroductionIslet xenotransplantation may be a therapeutic option in type 1 diabetes. Recent advances in generating genetically modified source pigs offer advantages as immune suppressants can potentially be eliminated after the transplantation. Therapy monitoring would greatly benefit from noninvasive methods for assessing the viability of transplanted islets. Peptide-based positron emission tomography (PET) targeting the glucagon-like peptide-1 receptor (GLP1R) expression on beta cells may offer a procedure that can directly be translated from an experimental setting to the clinic. The aim of this study was to establish the labeling of the GLP1R ligand [68Ga]Ga-exendin-4, to demonstrate the feasibility of imaging porcine islet xenografts in vivo and to compare signal quality for three different transplantation sites in a mouse model.Materials and methodsMice with engrafted neonatal porcine islet cell clusters (NPICCs) under the kidney capsule, into the inguinal fold, or the lower hindlimb muscle were studied. After reaching normoglycemia, the mice were injected with [68Ga]Ga-exendin-4 for PET data acquisition. Subsequent autoradiography (AR) was used for comparing ex vivo data with in vivo uptake.ResultsNPICCs in the lower right hindlimb muscle could be detected in vivo and in AR. Due to the high background in the kidney and urinary bladder, islets could not be detected in the PET data at transplantation sites close to these organs, while AR showed a clear signal for the islets in the inguinal fold.DiscussionPET with [68Ga]Ga-exendin-4 detects islets transplanted in the hindlimb muscle tissue of mice, offering the potential of longitudinal monitoring of viable porcine islets. Other sites are not suitable for in vivo imaging owing to high activity accumulation of Exendin-4 in kidney and bladder.

Purpose A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose. Methods Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) and 2-(5-[ 18 F]fluoropentyl)-2-methyl malonic acid ([ 18 F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results. Results The hematopoietic bone marrow showed a significantly increased [ 18 F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [ 18 F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [ 18 F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data. Conclusion [ 18 F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [ 18 F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [ 18 F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.

Ziel/Aim Ein Verfahren zur regionalen in vivo Darstellung strahleninduzierter Zellschäden könnte diagnostisch für Strahlennotfallpatienten bei zivilen wie auch militärischen Ereignissen von Nutzen sein. Ziel dieser Studie war die Untersuchung des Potentials von PET mit Apoptose- und Proliferationstracern im Mausmodell.

Neuronal lesions trigger mechanisms of structural and functional neuroplasticity, which can support recovery. However, the temporal and spatial appearance of structure–function changes and their interrelation remain unclear. The current study aimed to directly compare serial whole-brain in vivo measurements of functional plasticity (by [ 18 F]FDG-PET) and structural synaptic plasticity (by [ 18 F]UCB-H-PET) before and after bilateral labyrinthectomy in rats and investigate the effect of locomotor training. Complex structure–function changes were found after bilateral labyrinthectomy: in brainstem-cerebellar circuits, regional cerebral glucose metabolism (rCGM) decreased early, followed by reduced synaptic density. In the thalamus, increased [ 18 F]UCB-H binding preceded a higher rCGM uptake. In frontal-basal ganglia loops, an increase in synaptic density was paralleled by a decrease in rCGM. In the group with locomotor training, thalamic rCGM and [ 18 F]UCB-H binding increased following bilateral labyrinthectomy compared to the no training group. Rats with training had considerably fewer body rotations. In conclusion, combined [ 18 F]FDG/[ 18 F]UCB-H dual tracer imaging reveals that adaptive neuroplasticity after bilateral vestibular loss is not a uniform process but is composed of complex spatial and temporal patterns of structure–function coupling in networks for vestibular, multisensory, and motor control, which can be modulated by early physical training.

Ziel/Aim The purpose was to depict the spatial distribution and temporal scale of functional plasticity, estimated by regional glucose metabolism (rCGM), and structural plasticity, quantified by synaptic density, after bilateral labyrinthectomy (BL) and its modulation by physical training.

Receptor-specific peptides labeled with positron emitters play an important role in the clinical imaging of several malignancies by positron emission tomography (PET). Radiolabeled heterobivalent bispecific peptidic ligands (HBPLs) can target more than one receptor type and by this - besides exhibiting other advantages - increase tumor imaging sensitivity. In the present study, we show the initial in vivo evaluation of the most potent heterobivalent gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC1R)-bispecific radiotracer and determined its tumor visualization potential via PET/CT imaging. For this purpose, the most potent described HBPL was synthesized together with its partly scrambled heterobivalent monospecific homologs and its monovalent counterparts. The agents were efficiently labeled with 68Ga3+ and evaluated in an initial PET/CT tumor imaging study in a human prostate carcinoma (PCa) xenograft rat tumor model established for this purpose. None of the three 68Ga-HBPLs enabled a clear tumor visualization and a considerably higher involvement in receptor-mediated uptake was found for the GRPR-binding part of the molecule than for the VPAC1R-binding one. Of the monovalent radiotracers, only [68Ga]Ga-NODA-GA-PESIN could efficiently delineate the tumor, confirming the results. Thus, this work sets the direction for future developments in the field of GRPR- and VPAC1R-bispecific radioligands, which should be based on other VPAC1R-specific peptides than PACAP-27.

Neuronal lesions trigger mechanisms of structural and functional neuroplasticity, which can support recovery. However, the temporal and spatial appearance of structure-function changes and their interrelation remain unclear. The current study aimed to directly compare serial whole-brain in vivo measurements of functional plasticity (by [ 18 F]-FDG-PET) and structural synaptic plasticity (by [ 18 F]-UCB-H-PET) before and after bilateral labyrinthectomy in rats and investigate the effect of locomotor training. Complex structure-function changes were found after bilateral labyrinthectomy: in brainstem-cerebellar circuits, regional cerebral glucose metabolism (rCGM) decreased early, followed by reduced synaptic density. In the thalamus, increased [ 18 F]-UCB-H binding preceded a higher rCGM uptake. In frontal-basal ganglia loops, an increase in synaptic density was paralleled by a decrease in rCGM. In the group with locomotor training, thalamic rCGM and [ 18 F]-UCB-H binding increased following bilateral labyrinthectomy compared to the no training group. Rats with training had relatively fewer body rotations. In conclusion, combined [ 18 F]-FDG/[ 18 F]-UCB-H dual tracer imaging reveals that adaptive neuroplasticity after bilateral vestibular loss is not a uniform process but is composed of complex spatial and temporal patterns of structure-function coupling in networks for vestibular, multisensory, and motor control, which can be modulated by early physical training.

Ziel/Aim Nach einer akuten vestibulären Läsion bessert sich die Symptomatik innerhalb von Wochen durch die zentrale vestibuläre Kompensation (VC). Dabei kommt es zu einer transienten Gliaaktivierung im ipsiläsionalen vestibulären Kern (iVN), deren funktionelle Rolle unklar ist. In dieser Studie wurde untersucht, ob die Modulation der Gliaaktivierung durch den TSPO-Agonisten Etifoxin (ETX) einen Einfluss auf die symptomatische Erholung im Rattenmodell der unilateralen Labyrinthektomie (UL) hat. Zudem wurden die ETX–induzierten Effekte auf die Gliaaktivierung mittels [18F]GE180-µPET visualisiert.