Preclinical PET Imaging Research Articles

Preclinical Evaluation and Pilot Clinical Study of 18F-Labeled Inhibitor Peptide for Noninvasive Positron Emission Tomography Mapping of Angiotensin Converting Enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is the main molecular target for coronavirus SARS-CoV-2 to enter cells. Molecularly specific tracers that bind to ACE2 with high affinity can be used to determine the tissue distribution of this important receptor, noninvasively. A novel targeting PET imaging probe, [18F]AlF-DX600-BCH, was developed to detect the in vivo expression of ACE2 and monitor response to therapy. Preclinical experiments, including biodistribution, PET imaging, and tissue section analysis, were conducted after tests of in vitro and in vivo stability and pharmacokinetics. The agent was advanced to clinical evaluation in 10 volunteers who received [18F]AlF-DX600-BCH PET/CT at 1 and 2 h after injection (NCT04542863). Preclinical results of both biodistribution and PET demonstrated [18F]AlF-DX600-BCH accumulation in rat kidney (standardized uptake value; SUVkidney/normal > 50), along with specific uptake in testes (SUVtestis/normal > 10) tissues. Kidney, gastrointestinal, and bronchial cell labeling were correlated to ACE2 positive by immunohistochemistry (IHC) staining. In clinical imaging, significant tracer accumulation was predominantly observed in the urinary and reproductive system (SUVrenalcortex = 32.00, SUVtestis = 4.56), and the conjunctiva and nasal mucosa saw elevated uptake in several cases. This work is the first report of a radioisotope probe, [18F]AlF-DX600-BCH, targeting ACE2 with promising preliminary preclinical and translational outlook, thereby demonstrating the potential of noninvasive mapping of ACE2.

Characterization of IMIC, an implantable needle-shaped positron sensitive monolithic active pixel sensor for preclinical molecular neuroimaging

The correlation of molecular neuroimaging and behavior studies in preclinical PET imaging is of major interest to unlock progress in the understanding of brain processes and assess the validity of preclinical studies in drug development. However, fully achieving this ambition requires performing molecular images of awake and freely moving animals, whereas most of the preclinical imaging procedures are currently performed under anesthesia. To overcome this issue, the MAPSSIC project aims to develop a pixelated intracerebral probe to be implanted into awake and freely moving rats. The aforementioned probe relies on IMIC (Imageur Moléculaire Intra Cérébral), a Monolithic Active Pixel Sensor (MAPS) prototype set to directly detect positrons. The IMIC sensors were produced in 5 different configurations. Measurements using a 204Tl source showed that the sensor parameters can be optimized to boost its performance allowing to increase the sensitivity and reduce the average cluster size. In addition, comparisons between sensor configurations show a clear gain provided by the introduction of CMOS process modifications. Finally, the choice of the optimal sensor configuration will depend on the expected in vivo conditions.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4h post-injection. Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route

IntroductionCopper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. Methods64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. ResultsMaximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection. Conclusions64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. Advances in knowledge and implications for patient careOur 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.

Identification of a Putative α-synuclein Radioligand Using an in silico Similarity Search.

Previous studies from our lab utilized an ultra-high throughput screening method to identify compound 1 as a small molecule that binds to alpha-synuclein (α-synuclein) fibrils. The goal of the current study was to conduct a similarity search of 1 to identify structural analogs having improved in vitro binding properties for this target that could be labeled with radionuclides for both in vitro and in vivo studies for measuring α-synuclein aggregates. Using 1 as a lead compound in a similarity search, isoxazole derivative 15 was identified to bind to α-synuclein fibrils with high affinity in competition binding assays. A photocrosslinkable version was used to confirm binding site preference. Derivative 21, the iodo-analog of 15, was synthesized, and subsequently radiolabeled isotopologs [125I]21 and [11C]21 were successfully synthesized for use in in vitro and in vivo studies, respectively. [125I]21 was used in radioligand binding studies in post-mortem Parkinson's disease (PD) and Alzheimer's disease (AD) brain homogenates. In vivo imaging of an α-synuclein mouse model and non-human primates was performed with [11C]21. In silico molecular docking and molecular dynamic simulation studies for a panel of compounds identified through a similarity search, were shown to correlate with Ki values obtained from in vitro binding studies. Improved affinity of isoxazole derivative 15 for α-synuclein binding site 9 was indicated by photocrosslinking studies with CLX10. Design and successful (radio)synthesis of iodo-analog 21 of isoxazole derivative 15 enabled further in vitro and in vivo evaluation. Kd values obtained in vitro with [125I]21 for α-synuclein and Aβ42 fibrils were 0.48 ± 0.08 nM and 2.47 ± 1.30 nM, respectively. [125I]21 showed higher binding in human postmortem PD brain tissue compared with AD tissue, and low binding in control brain tissue. Lastly, in vivo preclinical PET imaging showed elevated retention of [11C]21 in PFF-injected mouse brain. However, in PBS-injected control mouse brain, slow washout of the tracer indicates high non-specific binding. [11C]21 showed high initial brain uptake in a healthy non-human primate, followed by fast washout that may be caused by rapid metabolic rate (21% intact [11C]21 in blood at 5 min p.i.). Through a relatively simple ligand-based similarity search, we identified a new radioligand that binds with high affinity (<10 nM) to α-synuclein fibrils and PD tissue. Although the radioligand has suboptimal selectivity for α-synuclein towards Aβ and high non-specific binding, we show here that a simple in silico approach is a promising strategy to identify novel ligands for target proteins in the CNS with the potential to be radiolabeled for PET neuroimaging studies.

Preclinical evaluation of theranostic strategy using nanoplatform and transferrin to target hyperactivity of cMYC in the context of non-small cell lung cancer

Non-small cell lung cancer affects 1.3 million people annually worldwide. The cMYC pathway regulates a large number of physiological processes and is hyperactivated in many cancers, including lung cancers. Due to the high avidity of cancer cells for iron, transferrin receptor complex (TFRC) has been demonstrated to be overexpressed when the cMYC pathway is hyperactivated. On this basis, there has been extensive interest in targeting TFRC therapeutically and in imaging TFRC expression. Our objective here is to develop a theranostic method targeting the transferrin receptor. We propose to target TFRC through a ligand scaffold based on a peptide able to be radiolabelled with either 18-Fluor (18F) for imaging or with 177-Lutetium (177Lu) for internal radiotherapy. To fully exploit the internal radiotherapy potential, nano-radioenhencer agent (platinum agent) will be used to exalt the irradiation impact. We radiolabelled the anti-TFRC peptide thanks to direct 18F labeling or via the conjugation of a chelate for 177Lu. We carried out in vitro tests to select a cell line overexpressing TFRC (human and murine). We evaluated the ability of the modified peptide to bind to TFRC thanks to binding assays. C57BL/6J mice were implanted with NSCLC (CMT167) or melanoma (B16F10) xenografts to establish the biodistribution of the new theranostic platform and the nanoparticles distribution. The distribution of the nanoparticles was also assessed by PET imaging. We radiolabelled and validated in vitro the functionality of the peptide with specific radiolabelling through a pyridine modified prosthetic group. The affinity of the modified peptide to TFRC remains sufficient to accumulate specifically within the tumor (Kd∼500 nM). We were able to assess the ability of the peptide to bind to TFRC by preclinical PET imaging through pharmacokinetic and biodistribution data. Nanoparticle presents a high tumor uptake (4.5%ID/cc, at 24 h). High liver TFRC expression can limit the performance of such cMYC theranostic platform. The peptide distribution may present some advantages to decreasing liver accumulation. The biodistribution and pharmacokinetics of either the nanoparticles or the peptides offer a promising therapeutic perspective. This novel therapeutic approach will have the potential to redirect the community's effort to ablative reagents that target downstream pathobiology regulated by cMYC.

Decreased synaptic vesicle glycoprotein 2A binding in a rodent model of familial Alzheimer's disease detected by [18F]SDM-16.

Synapse loss is one of the hallmarks of Alzheimer's disease (AD) and is associated with cognitive decline. In this study, we tested [18F]SDM-16, a novel metabolically stable SV2A PET imaging probe, in the transgenic APPswe/PS1dE9 (APP/PS1) mouse model of AD and age-matched wild-type (WT) mice at 12 months of age. Based on previous preclinical PET imaging studies using [11C]UCB-J and [18F]SynVesT-1 in the same strain animals, we used the simplified reference tissue model (SRTM), with brain stem as the pseudo reference region to calculate distribution volume ratios (DVRs). To simplify and streamline the quantitative analysis, we compared the standardized uptake value ratios (SUVRs) from different imaging windows to DVRs and found that the averaged SUVRs from 60-90 min post-injection (p.i.) are most consistent with the DVRs. Thus, we used averaged SUVRs from 60-90 min for group comparisons and found statistically significant differences in the tracer uptake in different brain regions, e.g., hippocampus (p = 0.001), striatum (p = 0.002), thalamus (p = 0.003), and cingulate cortex (p = 0.0003). In conclusion, [18F]SDM-16 was used to detect decreased SV2A levels in the brain of APP/PS1 AD mouse model at one year old. Our data suggest that [18F]SDM-16 has similar statistical power in detecting the synapse loss in APP/PS1 mice as [11C]UCB-J and [18F]SynVesT-1, albeit later imaging window (60-90 min p.i.) is needed when SUVR is used as a surrogate for DVR for [18F]SDM-16 due to its slower brain kinetics.

Preclinical PET and MR Evaluation of 89Zr- and 68Ga-Labeled Nanodiamonds in Mice over Different Time Scales.

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.

Proposal of Brazilian National Program for Quality Control in the small animal PET scanners

In Brazil, currently there are six preclinical molecular imaging centers and seven different small animal PET systems in use. However, there is still no national specific legislation for research laboratories focused on preclinical molecular images, unlike clinical nuclear medicine centers. A standardization of quality control protocols is needed to harmonize the use of small animal PET scanners in the research field. Thus, the aim of this work was to propose a National Program for Quality Control (NPQC) for the preclinical PET imaging systems in Brazil. This work was based on the quality control tests performed in Molecular Image Laboratory LIM/CDTN based on NEMA NU 4-2008 as described and presented in doctoral thesis of GONTIJO, 2019. The proposal of the NQCP was based on the CNEN NN 3.05 Publication (2013) and includes fundamental tests to be adopted, if possible, in laboratory practice to corroborate the experimental data. The Quality Control Program implemented in LIM/CDTN is an innovative and unprecedented proposal in the scope of preclinical molecular imaging services in Brazil. Therefore, the LIM/CDTN Program was carried out as a pilot to evidence the applicability and viability of the NQCP using small animal PET scanners. Summarizing, this work presents a viable set of Quality Control tests and their periodicities like a proposal for standardization to harmonize the use of this imaging technology in the field of research. Therefore, a National Quality Control Program (NQCP) applied to small animal PET scanners.

PET Imaging in Animal Models of Alzheimer's Disease.

The successful development and translation of PET imaging agents targeting β-amyloid plaques and hyperphosphorylated tau tangles have allowed for in vivo detection of these hallmarks of Alzheimer’s disease (AD) antemortem. Amyloid and tau PET have been incorporated into the A/T/N scheme for AD characterization and have become an integral part of ongoing clinical trials to screen patients for enrollment, prove drug action mechanisms, and monitor therapeutic effects. Meanwhile, preclinical PET imaging in animal models of AD can provide supportive information for mechanistic studies. With the recent advancement of gene editing technologies and AD animal model development, preclinical PET imaging in AD models will further facilitate our understanding of AD pathogenesis/progression and the development of novel treatments. In this study, we review the current state-of-the-art in preclinical PET imaging using animal models of AD and suggest future research directions.

O-25 - Preclinical PET imaging of GSK-3 in pancreatic cancer

O-25 - Preclinical PET imaging of GSK-3 in pancreatic cancer

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging.

The development of novel PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A) allowed for the in vivo detection of synaptic density changes, which are correlated with the progression and severity of a variety of neuropsychiatric diseases. While multiple ongoing clinical investigations using SV2A PET are expanding its applications rapidly, preclinical SV2A PET imaging in animal models is an integral component of the translation research and provides supporting and complementary information. Herein, we overview preclinical SV2A PET studies in animal models of neurodegenerative disorders and discuss the opportunities and practical challenges in small animal SV2A PET imaging. At the Yale PET Center, we have conducted SV2A PET imaging studies in animal models of multiple diseases and longitudinal SV2A PET allowed us to evaluate synaptic density dynamics in the brains of disease animal models and to assess pharmacological effects of novel interventions. In this article, we discuss key considerations when designing preclinical SV2A PET imaging studies and strategies for data analysis. Specifically, we compare the brain imaging characteristics of available SV2A tracers, i.e., [11C]UCB-J, [18F]SynVesT-1, [18F]SynVesT-2, and [18F]SDM-16, in rodent brains. We also discuss the limited spatial resolution of PET scanners for small brains and challenges of kinetic modeling. We then compare different injection routes and estimate the maximum throughput (i.e., number of animals) per radiotracer synthesis by taking into account the injectable volume for each injection method, injected mass, and radioactivity half-lives. In summary, this article provides a perspective for designing and analyzing SV2A PET imaging studies in small animals.

Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer.

Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.

Evaluation of the spline reconstruction technique for preclinical PET imaging

Background and ObjectiveThe Spline Reconstruction Technique (SRT) is a fast algorithm based on a novel numerical implementation of an analytic representation of the inverse Radon transform. The purpose of this study is to provide a comparison between SRT, Filtered Back-Projection (FBP), Ordered Subset Expectation Maximization 2D (2D-OSEM), and the Tera-Tomo 3D algorithm, using phantom data at various acquisition durations as well as small-animal data obtained from the Mediso nanoScan® PET/CT scanner. MethodsFor this purpose, the “NEMA NU 4–2008 standards” protocol was employed at five different realizations and acquisition durations. In addition to the image quality metrics described by the NEMA protocol, Cold Region Contrast was also considered as a figure-of-merit. Furthermore, Cold Region Contrast was measured in the myocardial infarction region of six male Wistar rats. The volumetric defect quantification was assessed with dedicated computer software. Lastly, plots of Recovery Coefficient and Spill-Over Ratio as a function of the Percentage Standard Deviation were generated, after smoothing the phantom reconstructions with four different Gaussian filters. Statistical significance was determined by employing the Kruskal-Wallis test or One-way Analysis of Variance depending on the normality of the variable's distribution. ResultsThe present study revealed that, at the expense of slightly increased noise in the reconstructed images, SRT resulted in higher Recovery Coefficient values for small hot regions of interest, when compared with FBP and 2D-OSEM at all acquisition durations. Furthermore, SRT reconstructed images exhibit higher Recovery Coefficient values, for all hot regions of interest, when compared to the other 2D algorithms at short acquisition durations. In both phantom and animal studies, SRT achieved a significant improvement over 2D-OSEM for the Spill-Over Ratio and the Cold Region Contrast. These advantages were maintained even after comparing the algorithms at equal noise levels. The Tera-Tomo 3D algorithm (4 subsets, iterations≥ 13) performed significantly better compared to the other algorithms for all figures-of-merit. No statistically significant differences regarding the myocardial defect size were observed between the algorithms investigated. ConclusionsOverall, SRT appears that could be useful for the quantification of small hot regions of interest, cold regions of interest, as well as in low-count imaging applications.

Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model.

Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression.MethodsPharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (μPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans.ResultsOrgan distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 μSv/MBq.ConclusionThe predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.

Compensating Positron Range Effects of Ga-68 in Preclinical PET Imaging by Using Convolutional Neural Network: A Monte Carlo Simulation Study.

This study aimed to investigate the feasibility of positron range correction based on three different convolutional neural network (CNN) models in preclinical PET imaging of Ga-68. The first model (CNN1) was originally designed for super-resolution recovery, while the second model (CNN2) and the third model (CNN3) were originally designed for pseudo CT synthesis from MRI. A preclinical PET scanner and 30 phantom configurations were modeled in Monte Carlo simulations, where each phantom configuration was simulated twice, once for Ga-68 (CNN input images) and once for back-to-back 511-keV gamma rays (CNN output images) with a 20 min emission scan duration. The Euclidean distance was used as the loss function to minimize the difference between CNN input and output images. According to our results, CNN3 outperformed CNN1 and CNN2 qualitatively and quantitatively. With regard to qualitative observation, it was found that boundaries in Ga-68 images became sharper after correction. As for quantitative analysis, the recovery coefficient (RC) and spill-over ratio (SOR) were increased after correction, while no substantial increase in coefficient of variation of RC (CVRC) or coefficient of variation of SOR (CVSOR) was observed. Overall, CNN3 should be a good candidate architecture for positron range correction in Ga-68 preclinical PET imaging.

Leveraging deep neural networks to improve numerical and perceptual image quality in low-dose preclinical PET imaging.

The amount of radiotracer injected into laboratory animals is still the most daunting challenge facing translational PET studies. Since low-dose imaging is characterized by a higher level of noise, the quality of the reconstructed images leaves much to be desired. Being the most ubiquitous techniques in denoising applications, edge-aware denoising filters, and reconstruction-based techniques have drawn significant attention in low-count applications. However, for the last few years, much of the credit has gone to deep-learning (DL) methods, which provide more robust solutions to handle various conditions. Albeit being extensively explored in clinical studies, to the best of our knowledge, there is a lack of studies exploring the feasibility of DL-based image denoising in low-count smallanimal PET imaging. Therefore, herein, we investigated different DL frameworks to map low-dose smallanimal PET images to their full-dose equivalent with quality and visual similarity on a par with those of standard acquisition. The performance of the DL model was also compared to other well-established filters, including Gaussian smoothing, nonlocal means, and anisotropic diffusion. Visual inspection and quantitative assessment based on quality metrics proved the superior performance of the DL methods in low-count smallanimal PET studies, paving the way for a more detailed exploration of DL-assisted algorithms in this domain.

Receptor mapping using methoxy phenyl piperazine derivative: Preclinical PET imaging

This study aimed at assessing 2-methoxyphenyl piperazine derivative for its binding specificity and suitability in mapping metabotropic glutamate receptor subtype 1, which is implicated in several neuropsychiatric disorders. N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)-N-methylpyridin-2-amine was synthesised and evaluated for brain imaging subsequent to radiolabelling with [11C] radioisotope via methylation process in 98.9% purity and 52 ± 6% yield (decay corrected). The specific activity was in the range of 72–93 GBq/µmol. The haemolysis of blood was 2–5% for initial 4 hr and remained < 10% after 24 h of incubation indicating low toxicity. In vitro autoradiograms after coincubation with unlabelled ligand confirmed the high uptake of the PET radioligand in the mGluR1 receptor rich regions.The PET as well as biodistribution studies also showed high activity in the brain with a direct correlation between receptor abundance distribution pattern and tracer activity. The biodistribution analyses revealed initial high brain uptake (4.18 ± 0.48). The highest uptake was found in cerebellum (SUV 4.7 ± 0.2), followed by thalamus (SUV 3.5 ± 0.1), and striatum (SUV 3 ± 0.1). In contrast, pons had negligible tracer activity. The high uptake observed in all the regions with known mGluR1 activity indicates suitability of the ligand for mGluR1 imaging.

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the \u201cCancer Integrin\u201d \u03b1v\u03b26 with Ga-68-Trivehexin

PurposeTo develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas.MethodsGa-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC.ResultsGa-68-Trivehexin showed a high αvβ6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation.ConclusionsGa-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

First InVivo and Phantom Imaging of Cyclotron-Produced 133La as a Theranostic Radionuclide for 225Ac and 135La.

Theranostic isotope pairs have gained recent clinical interest because they can be labeled to the same tracer and applied for diagnostic and therapeutic purposes. The goals of this study were to investigate cyclotron production of clinically relevant 133La activities using natural and isotopically enriched barium target material, compare fundamental PET phantom imaging characteristics of 133La with those of common PET radionuclides, and demonstrate invivo preclinical PET tumor imaging using 133La-PSMA-I&T. Methods:133La was produced on a 24-MeV cyclotron using an aluminum-indium sealed target with 150-200 mg of isotopically enriched 135BaCO3, natBaCO3, and natBa metal. A synthesis unit performed barium/lanthanum separation. DOTA, PSMA-I&T, and macropa were radiolabeled with 133La. Derenzo and National Electrical Manufacturers Association phantom imaging was performed with 133La, 132La, and 89Zr and compared with 18F, 68Ga, 44Sc, and 64Cu. In vivo preclinical imaging was performed with 133La-PSMA-I&T on LNCaP tumor-bearing mice. Results: Proton irradiations for 100 µA·min at 23.3 MeV yielded 214 ± 7 MBq of 133La and 28 ± 1 MBq of 135La using 135BaCO3, 59 ± 2 MBq of 133La and 35 ± 1 MBq of 135La using natBaCO3, and 81 ± 3 MBq of 133La and 48 ± 1 MBq of 135La using natBa metal. At 11.9 MeV, 135La yields were 81 ± 2 MBq, 6.8 ± 0.4 MBq, and 9.9 ± 0.5 MBq for 135BaCO3, natBaCO3, and natBa metal. BaCO3 target material recovery was 95.4% ± 1.7%. National Electrical Manufacturers Association and Derenzo phantom imaging demonstrated that 133La PET spatial resolution and scanner recovery coefficients were superior to those of 68Ga and 132La and comparable to those of 89Zr. The apparent molar activity was 130 ± 15 GBq/µmol with DOTA, 73 ± 18 GBq/µmol with PSMA-I&T, and 206 ± 31 GBq/µmol with macropa. Preclinical PET imaging with 133La-PSMA-I&T provided high-resolution tumor visualization with an SUV of 0.97 ± 0.17 at 60 min. Conclusion: With high-yield 133La cyclotron production, recovery of BaCO3 target material, and fundamental imaging characteristics superior to those of 68Ga and 132La, 133La represents a promising radiometal candidate to provide high-resolution PET imaging as a PET/α-therapy theranostic pair with 225Ac or as a PET/Auger electron therapy theranostic pair with 135La.