[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience

Purpose The clinical success non-invasive imaging of CXCR4 expression using [(68) Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of Tc-99m-labeled cyclic pentapeptides based on the PentixaFor scaffold.Methods Six mas(3)-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa(3) linkers (L1-L6) as well as the corresponding HYNIC- and N-4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC(50)inv) were carried out using Jurkat T cell lymphoma cells and [I-125]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [Tc-99m]Tc-N-4-L6-CPCR4 ([Tc-99m]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [Tc-99m]Tc-N-4-L6-CPCR4 SPECT/planar imaging with individual dosimetry.Results Of the six mas(3)-conjugated peptides, mas(3)-L6-CPCR4 (mas(3)-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 & PLUSMN; 1.3 nM). Conjugation with N-4 (N-4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 & PLUSMN; 0.1 nM. [Tc-99m]Tc-N-4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 & PLUSMN; 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [Tc-99m]Tc-N-4-L6-CPCR4 (termed [Tc-99m]Tc-PentixaTec) was selected for first-in-human application. [Tc-99m]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.Conclusion The successive optimization of the amino acid composition of the linker structure and the N-terminal Tc-99m-labeling strategies (mas(3) vs HYNIC vs N-4) has provided [Tc-99m]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use

Convolutional neural networks for automatic image quality control and EARL compliance of PET images

Background: Machine learning studies require a large number of images often obtained on different PET scanners. When merging these images, the use of harmonized images following EARL-standards is essential. However, when including retrospective images, EARL accreditation might not have been in place. The aim of this study was to develop a convolutional neural network (CNN) that can identify retrospectively if an image is EARL compliant and if it is meeting older or newer EARL-standards. Materials and methods: 96 PET images acquired on three PET/CT systems were included in the study. All images were reconstructed with the locally clinically preferred, EARL1, and EARL2 compliant reconstruction protocols. After image pre-processing, one CNN was trained to separate clinical and EARL compliant reconstructions. A second CNN was optimized to identify EARL1 and EARL2 compliant images. The accuracy of both CNNs was assessed using fivefold cross-validation. The CNNs were validated on 24 images acquired on a PET scanner not included in the training data. To assess the impact of image noise on the CNN decision, the 24 images were reconstructed with different scan durations. Results: In the cross-validation, the first CNN classified all images correctly. When identifying EARL1 and EARL2 compliant images, the second CNN identified 100% EARL1 compliant and 85% EARL2 compliant images correctly. The accuracy in the independent dataset was comparable to the cross-validation accuracy. The scan duration had almost no impact on the results. Conclusion: The two CNNs trained in this study can be used to retrospectively include images in a multi-center setting by, e.g., adding additional smoothing. This method is especially important for machine learning studies where the harmonization of images from different PET systems is essential

Automatic covariance pattern analysis outperforms visual reading of 18 F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) in variant progressive supranuclear palsy

Background: To date, studies on positron emission tomography (PET) with F-18-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). Objectives: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. Results: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. Conclusions: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. (C) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Prompt gamma spectroscopy for range control with CeBr3

The ultimate goal of radiotherapy using external beams is to maximize the dose delivered to the tumor while minimizing the radiation given to surrounding healthy critical organs. Prompt Gamma Spectroscopy (PGS) has been proposed for range control of particle beams along with the determination of the elemental composition of irradiated tissues. We aim at developing a PGS system for the German Cancer Research Center – DKFZ that takes advantage of the superior selectivity of Helium and Carbon beams accelerated at the Heidelberg Ion-Beam Therapy Center. Preliminary tests with protons accelerated with an IBA C230 cyclotron located at the Universitäts Protonen Therapie Dresden were performed at OncoRay – National Center for Radiation Re-search in Oncology. We present results obtained with a PGS system composed of CeBr3 detectors (Ø 2’’ × 2’’) and (Ø 1.5’’ × 3’’) coupled to a Hamamatsu R13089 photomulti-plier tube and plugged to a Target U100 Spectrometer. Such system provides accurate time-of-flight measurements to increase the signal-to-noise ratio relative to neutron-induced background. First measurements resulted from the irradiation of PMMA and water phantoms, and graphite and aluminum bricks. Several PG energy lines ranging from 0.511 MeV up to 8 MeV were identified and compared with reference re-sults. Two further experiments consisted in irradiating PMMA phantoms in a slit- and semi-collimated configuration with mono-energetic proton beams of 165 MeV and 224 MeV, respectively. Results acquired by means of trans-versal PGS at different phantom depths, ranging from 6 cm before the Bragg peak (BP) to 3.5 cm beyond the BP in 5 mm steps with a 1 cm slit collimation (tungsten) showed a slight decrease of PG yields after the BP. Similar measurements with a semi-opened collimation configuration demonstrated a steeper decrease of PG yields after the BP

Radiation doses from low-dose CT scans in SPECT/CT and PET/CT examinations: A survey in Germany

Aim Recently, dose reference levels (DRLs) have been defined in Germany for auxiliary low-dose CT scans in hybrid SPECT/CT and PET/CT examinations, based on data from 2016/17. Here, another survey from 2020 was evaluated and compared with the new DRLs as well as with similar surveys from foreign countries. Methods The survey, which had already been conducted in the Nordic countries, queried for various examinations including the following values: patient weight and height, volume CT dose index (CTDI (vol) ), dose length product (DLP). For each examination, statistical parameters such as the third quartile (Q3) were determined from all submitted CTDI (vol) and DLP values. Additionally, for examinations comprising datasets from at least 10 systems, the third quartile (Q3-Med) of the respective median values of each system was calculated. Q3 and Q3-Med were compared with the newly published DRLs from Germany and values from similar studies from other countries. Results Data from 15 SPECT/CT and 13 PET/CT systems from 15 nuclear medicine departments were collected. For the following examinations datasets from more than 10 systems were submitted: SPECT lung VQ, SPECT bone, SPECT&PET cardiac, PET brain, PET oncology. Especially for examinations of the thorax and heart, the new DRLs are very strict compared to this study. The CTDI (vol) values for examinations of the head were lower in this study than the DRLs prescribe now. Conclusions For certain examination types, there is a need for dose optimization at some clinics and devices in order to take into account the new DRLs in Germany in the future