Background: The reference for imaging in neurodegenerative dementia syndromes (NDS) is [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Advanced multimodal magnetic resonance imaging (MRI) may complement PET-derived measures for differential diagnostics. Objectives: The aim of the present study was to evaluate a new methodological approach integrating metabolic, perfusion, and microstructural parameters from simultaneous FDG-PET/MRI to reveal different imaging signatures for different NDS subtypes. Materials and Methods: 66 patients with NDS (Alzheimer’s disease: 28; behavioral frontotemporal dementia: 10; semantic variant primary progressive aphasia (PPA): 8; non-fluent variant PPA: 11; logopenic variant PPA: 9) and 10 subjects with subjective cognitive deficits (SCD) underwent combined FDG-PET/MRI with pseudo-continuous arterial spin labeling (pCASL) and diffusion tensor imaging (DTI). Standardized uptake values (SUV), cerebral blood flow (CBF), and fractional anisotropy (FA) were used to separate a respective NDS subgroup from all other NDS subgroups and from SCD based on a support vector machine (SVM) applied on region of interest (ROI)-based parameters. Results: White matter alterations directly adjacent to the regions of alterations in SUV and CBF were identified. The SVM analysis on ROI-based parameters reached accuracies between 81% and 94% for separating an NDS subgroup from all other NDS subgroups and from SCD. Conclusions: Multimodal neuroimaging by combination of FDG-PET and MRI shows potential to further advance the diagnostic spectrum in NDS. Since particularly early diagnosis of NDS remains key for effective treatment and management of patients with NDS, the present framework appears promising to be developed further until it aligns and integrates with clinical routine.

Silicon-based ligands are of interest in increasingly used Prostate-specific membrane antigen (PSMA) tracers for prostate cancer (PCa) staging due to their simple and scalable production. Here, we present first data on dosimetry and biodistribution of the novel PSMA-specific tracer [¹⁸F]siPSMA-14.Seven PCa patients referred for PSMA-PET/CT imaging were imaged at 60 and 120 min p.i. (T1 and T3), without forced diuresis, to assess organ absorbed (AD) and effective doses (ED). We matched seven of subsequent 134 patients imaged at 90 min. p. i. (T2) to the initial seven patients according to disease and patient characteristics. SUVs of organs and PCa lesions as well as target-to-non-target ratios (TnTR) were analyzed. Statistical analysis was done using paired t-tests and Mann-Whitney U tests.[¹⁸F]siPSMA-14 dosimetry showed an ED of 1.95E-02±0.25E-02 mSv/MBq with the highest AD in kidneys (1.40E-01±0.41E-01 mGy/MBq). Tracer uptake in lesions (SUVmax±SD) was intense in all patients and increased significantly over time (local lesions (intraprostatic lesions or local recurrences) T1: 10.6±4.5; T3: 14.0±5.9 (p=0.01); metastatic lesions: T1: 17.7±8.9; T3: 20.6±9.4 (p=0.01). PCa uptake at T2 was similar, without significant difference in interindividual comparison in local (T1 to T2: p=0.39; T2 to T3: p=1.0) and metastatic lesions (T1 to T2: p=0.79; T2 to T3: p=0.43).[¹⁸F]siPSMA-14 showed moderate effective doses comparable to other 18F- and 68Ga-labeled PCa tracers even without forced diuresis. Uptake in PCa lesions was high and in line with data for other PSMA specific tracers. This suggests that PET imaging with[¹⁸F]siPSMA-14 is safe and effective even without forced diuresis with the advantage of a simple and scalable production.

Accurately diagnosing Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) is challenging due to overlapping symptoms and limitations of current imaging methods. This study investigates the use of [11C]PBB3 PET/CT imaging to visualize tau pathology and improve diagnostic accuracy. Given diagnostic challenges with symptoms and conventional imaging, [11C]PBB3 PET/CT’s potential to enhance accuracy was investigated by correlating tau pathology with cerebrospinal fluid (CSF) biomarkers, positron emission tomography (PET), computed tomography (CT), amyloid-beta, and Mini-Mental State Examination (MMSE). We conducted [11C]PBB3 PET/CT imaging on 24 patients with suspected AD or FTLD, alongside [11C]PiB PET/CT (13 patients) and [18F]FDG PET/CT (15 patients). Visual and quantitative assessments of [11C]PBB3 uptake using standardized uptake value ratios (SUV-Rs) and correlation analyses with clinical assessments were performed. The scans revealed distinct tau accumulation patterns; 13 patients had no or faint uptake (PBB3-negative) and 11 had moderate to pronounced uptake (PBB3-positive). Significant inverse correlations were found between [11C]PBB3 SUV-Rs and MMSE scores, but not with CSF-tau or CSF-amyloid-beta levels. Here, we show that [11C]PBB3 PET/CT imaging can reveal distinct tau accumulation patterns and correlate these with cognitive impairment in neurodegenerative diseases. Our study demonstrates the potential of [11C]PBB3-PET imaging for visualizing tau pathology and assessing disease severity, offering a promising tool for enhancing diagnostic accuracy in AD and FTLD. Further research is essential to validate these findings and refine the use of tau-specific PET imaging in clinical practice, ultimately improving patient care and treatment outcomes.

Mouse models are commonly used to study the biodistribution of novel radioligands, but alternative models corresponding to the 3Rs principles, such as the chorioallantoic membrane (CAM) model, are highly required. While there are promising data from the CAM model regarding target-specific radiolabeled compounds, its utility for assessing macromolecule biodistribution and analyzing the EPR effect remains to demonstrated. Using 89Zr-labeled human serum albumin, the accumulation of nontarget-specific macromolecules in CAM and mouse xenograft models was studied using PET and MRI. Therefore, the radioligand [89Zr]Zr-DFO-HSA was analyzed in both chicken embryos (n = 5) and SCID mice (n = 4), each with TZM-bl and PC-3 tumor entities. Dynamic PET and anatomical MRI, as well as ex vivo biodistribution analyses, were performed to assess ligand distribution over 24 h. Histological staining and autoradiography verified the intratumoral accumulation. The tumors were successfully visualized for CAM and mouse models by PET, and the albumin influx from the blood into the respective tumors did not differ significantly. The accumulation and retention of HSA in tumors due to the EPR effect was demonstrated for both models. These results highlight that the CAM model is a potential alternative to the mouse model for initial studies with novel radiolabeled macromolecules with respect to the 3Rs principles.

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of 90Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [90Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Die sachkundige Person in der Radiopharmakaherstellung benötigt neben theoretischen Kenntnissen auch einen Nachweis einer mehrjährigen praktischen Tätigkeit. Die Autoren erörtern in diesem Artikel, ob die praktische Tätigkeit zwingend in einem Betrieb abgeleistet werden muss, der über eine Herstellungserlaubnis verfügt.

Ziel/Aim Für in vivo Analysen neuartiger Radioliganden werden in der Regel Maus-Xenograft-Modelle herangezogen. Im Sinne der 3R-Prinzipien wurde in dieser Studie das Chorioallantoismembran- (CAM) Modell als potenzielle Alternative zur Analyse der Verteilung ungerichteter Makromoleküle verwendet. Die Kinetik von Zirkonium-89-markiertem humanem Serumalbumin (HSA) wurde dafür sowohl im CAM- als auch im Maus-Modell mittels PET und MRT verglichen.

Purpose The recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET. Materials and methods A total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aβ42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses. Results Seven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis. Conclusion Our results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

Background PSMA-TO-1 (“Tumor-Optimized-1”) is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68 Ga and 177 Lu, and the survival after treatment with 225 Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177 Lu-PSMA-TO1/-617 in prostate cancer patients. Methods First, PET images of 68 Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177 Lu-PSMA-617 or 177 Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225 Ac-PSMA-617, 225 Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177 Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations. Results Tumor uptake measured by PET imaging of 68 Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177 Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment ( p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225 Ac-PSMA-TO-1 survived longer than those treated with 225 Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p < 0.0001). Kidney, salivary gland, bone marrow and mean ± SD tumor dose coefficients (Gy/GBq) for 177 Lu-PSMA-TO-1 in patients #01/#02/#03 were 2.5/2.4/3.0, 1.0/2.5/2.3, 0.14/0.11/0.10 and 0.42 ± 0.03/4.45 ± 0.07/1.8 ± 0.57, respectively. Conclusions PSMA-TO-1 tumor uptake tended to be greater than that of PSMA-617 in both preclinical and clinical settings. Mice treated with 225 Ac-PSMA-TO-1 conferred a significant survival benefit compared to 225 Ac-PSMA-617 despite the accompanying increased kidney uptake. In humans, PSMA-TO-1 dosimetry estimates suggest increased tumor absorbed doses; however, the kidneys, salivary glands and bone marrow are also exposed to higher radiation doses. Thus, additional preclinical studies are needed before further clinical use.

Inhibition studies in small animals are the standard for evaluating the specificity of newly developed drugs, including radiopharmaceuticals. Recently, it has been reported that the tumor accumulation of radiotracers can be assessed in the chorioallantoic membrane (CAM) model with similar results to experiments in mice, such contributing to the 3Rs principles (reduction, replacement, and refinement). However, inhibition studies to prove receptor-specific binding have not yet been performed in the CAM model. Thus, in the present work, we analyzed the feasibility of inhibition studies in ovo by PET and MRI using the PSMA-specific ligand [18F]siPSMA-14 and the corresponding inhibitor 2-PMPA. A dose-dependent blockade of [18F]siPSMA-14 uptake was successfully demonstrated by pre-dosing with different inhibitor concentrations. Based on these data, we conclude that the CAM model is suitable for performing inhibition studies to detect receptor-specific binding. While in the later stages of development of novel radiopharmaceuticals, testing in rodents will still be necessary for biodistribution analysis, the CAM model is a promising alternative to mouse experiments in the early phases of compound evaluation. Thus, using the CAM model and PET and MR imaging for early pre-selection of promising radiolabeled compounds could significantly reduce the number of animal experiments.

Nanodiamonds (NDs) have high potential as a drug carrier and in combination with nitrogen vacancies (NV centers) for highly sensitive MR-imaging after hyperpolarization. However, little remains known about their physiological properties in vivo. PET imaging allows further evaluation due to its quantitative properties and high sensitivity. Thus, we aimed to create a preclinical platform for PET and MR evaluation of surface-modified NDs by radiolabeling with both short- and long-lived radiotracers. Serum albumin coated NDs, functionalized with PEG groups and the chelator deferoxamine, were labeled either with zirconium-89 or gallium-68. Their biodistribution was assessed in two different mouse strains. PET scans were performed at various time points up to 7 d after i.v. injection. Anatomical correlation was provided by additional MRI in a subset of animals. PET results were validated by ex vivo quantification of the excised organs using a gamma counter. Radiolabeled NDs accumulated rapidly in the liver and spleen with a slight increase over time, while rapid washout from the blood pool was observed. Significant differences between the investigated radionuclides were only observed for the spleen (1 h). In summary, we successfully created a preclinical PET and MR imaging platform for the evaluation of the biodistribution of NDs over different time scales.

Abstract In an end-stage midgut neuroendocrine tumor patient with carcinoid heart disease, right ventricular dysfunction, mildly reduced renal function, and refractory to 6 cycles of 177Lu-HA-DOTATATE therapy, planar, and 22 hours SPECT/CT images were acquired after injection of 224 MBq of 203Pb-VMT-α-NET to assess the feasibility of performing 212Pb-VMT-α-NET therapy. A comparison of the 1.5 and 22 hours SPECT/CT images with 68Ga-HA-DOTATATE PET/CT showed high uptake of 203Pb-VMT-α-NET in liver metastases matching with the results of the PET/CT investigation.

Background Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects.