Positron-emitting Isotopes Research Articles

Research of Potential Production 94mTc in Medical Cyclotron

To expand the spectrum of used radiopharmaceuticals, it is proposed to obtain a positron-emitting isotope of technetium 94mTc. The intention of this work is to research the possibility of producing various technetium isotopes on a medical cyclotron. For this purpose, we carried out a series of irradiations of an aqueous solution of molybdenum of natural isotopic composition with protons of 11 MeV energy. After technetium isolation, results were analyzed on a γ-spectrometer. 511 keV gamma-ray line was obtained.

Feasibility of using radiolabeled nitrogen-13 to track nitrogen kinetics in rodents exposed to hyperoxia or hyperbaric pressure.

Decompression sickness occurs from tissue supersaturation with nitrogen when pressure is reduced. It limits operational capacity in diving, aviation and extravehicular activity in space. Little is known about organ variability, and why differences exist between individuals. Procedures are based on empirical testing and mathematical modelling, with limited data from actual nitrogen load or diffusivity. Nitrogen has a positron-emitting isotope that can be made in gaseous form ( 13 N 2 ) which can then be monitored spatially and temporally. The feasibility to study nitrogen kinetics was assessed using hyperbaric pressure to increase the partial pressure or pre-breathing oxygen to increase tissue uptake capacity, both of which would expect to cause increased nitrogen uptake. Fifteen female Sprague Dawley rats were divided into air-breathing normobaric (CON), oxygen-breathing, including 1 h pre-breathing (OXY), and air-breathing hyperbaric, compressed to 700 kPa (HB). Breathing gases were supplemented with trace amounts of 13 N 2 for 30 min, with CON & OXY euthanized at 30 min. HB were decompressed and breathed air/isoflurane without 13 N 2 for 10-15 minutes before euthanized. Blood, liver, brain, femur (bone) and thigh muscle were analyzed in a gamma counter with the 13 N 2 counts normalized for organ mass. In liver (p=.026) and brain (p=.018) 13 N 2 was greater in OXY than both CON and HB. In the femur HB was higher than CON (p=.048). Results suggest that pre‑breathing O2 in OXY removed tissue nitrogen creating a larger gradient for 13 N 2 uptake. We interpret the limited increase in 13 N 2 in HB was due to off-gassing in high-perfused tissues during decompression, with the high femur value being due to uptake in HB but slower off-gassing during decompression. Our data suggest that 13 N 2 can be used to track gas kinetics in a live rodent during physiological conditions endured by humans. This study was supported by a grant from the Office of Naval Research. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PET radiotracers for whole-body in vivo molecular imaging of prostatic neuroendocrine malignancies.

Prostatic neuroendocrine malignancies represent a spectrum of diseases. Treatment-induced neuroendocrine differentiation (tiNED) in hormonally treated adenocarcinoma has been the subject of a large amount of recent research. However, the identification of neuroendocrine features in treatment-naïve prostatic tumor raises a differential diagnosis between prostatic adenocarcinoma with de novo neuroendocrine differentiation (dNED) versus one of the primary prostatic neuroendocrine tumors (P-NETs) and carcinomas (P-NECs). While [18F]FDG is being used as the main PET radiotracer in oncologic imaging and reflects cellular glucose metabolism, other molecules labeled with positron-emitting isotopes, mainly somatostatin-analogues labeled with 68Ga and prostate-specific membrane antigen (PSMA)-ligands labeled with either 18F or 68Ga, are now routinely used in departments of nuclear medicine and molecular imaging, and may be advantageous in imaging prostatic neuroendocrine malignancies. Still, the selection of the preferred PET radiotracer in such cases might be challenging. In the current review, we summarize and discuss published data on these different entities from clinical, biological, and molecular imaging standpoints. Specifically, we review the roles that [18F]FDG, radiolabeled somatostatin-analogues, and radiolabeled PSMA-ligands play in these entities in order to provide the reader with practical recommendations regarding the preferred PET radiotracers for imaging each entity. In cases of tiNED, we conclude that PSMA expression may be low and that [18F]FDG or radiolabeled somatostatin-analogues should be preferred for imaging. In cases of prostatic adenocarcinoma with dNED, we present data that support the superiority of radiolabeled PSMA-ligands. In cases of primary neuroendocrine malignancies, the use of [18F]FDG for imaging high-grade P-NECs and radiolabeled somatostatin-analogues for imaging well-differentiated P-NETs is recommended. KEY POINTS: • The preferred PET radiotracer for imaging prostatic neuroendocrine malignancies depends on the specific clinical scenario and pathologic data. • When neuroendocrine features result from hormonal therapy for prostate cancer, PET-CT should be performed with [18F]FDG or radiolabeled somatostatin-analogue rather than with radiolabeled PSMA-ligand. • When neuroendocrine features are evident in newly diagnosed prostate cancer, differentiating adenocarcinoma from primary neuroendocrine malignancy is challenging but crucial for selection of PET radiotracer and for clinical management.

Development of Tracer Particles for Positron Emission Particle Tracking

Positron Emission Particle Tracking (PEPT) is a radioactive tracer-based approach to studying dynamic physical processes and multiphase flows. Short-lived positron-emitting isotopes are loaded onto suitable substrates used as tracer particle flow followers in physical and engineering-relevant systems. Coincident photons from electron-positron annihilation are detected using large arrays of pixelated scintillators, with the reconstructed photon trajectories collectively used to determine tracer particle dynamics. We have developed indirect radiochemical, and direct physical activation, techniques for producing tracer particles for such studies, and we report on the current state of the art with focus on the direct approach with high-energy alpha-particle beams. The 16O(α,x)18F reactions have been explored as viable candidates in producing the pure positron emitter 18F from natural 16O-bearing targets. Silicon dioxide (SiO2) glass spheres of diameters of 5 to 10 mm were irradiated in a 100-MeV alpha-particle beam of around 800-nA current for approximately 2 h. Radioisotope activation yields were characterized by half-life measurements and gamma-ray spectroscopy, with the highest yield being 18F (<2.5 mCi). Contaminants from other reaction channels were observed and characterized, including the positron emitter 43Sc and negative beta emitter 24Na, produced from alpha and neutron activation of contaminant species in the target material, respectively. The activation technique is shown to be a reasonable candidate to complement and enhance existing tracer particle production techniques for PEPT and other radiotracer-based studies.

Synthesis and characterization of a novel [52Mn]Mn-labelled affibody based radiotracer for HER2+ targeting

Affibody linked to a rigid macrocyclic chelator derived form pyclen-3,9-diacetate (3,9-PC2A) labelled with [52Mn]Mn isotope appears to be a valuable tool for PET-based targeted molecular imaging.

Precision of the PET activity range during irradiation with 10C, 11C, and 12C beams

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable 12C ions, the positron emitters 10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam. Approach. An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner. Main results. High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes 11C and 10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107 ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for 10C, 11C and 12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from 11C to 10C than when going from 12C to 11C. The much better precision for 10C is due to its much shorter half-life, which, contrary to the case of 11C, also enables to include the in-spill data in the image formation. Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

MA09.05 Increased PD-L1 Tracer Uptake in Recently-irradiated Lesions in NSCLC: Preliminary Results of a Phase 0 Trial (ImmunoPET) of a Novel PET Tracer

A clinical trial was initiated to investigate the safety and optimum scanning protocol for a novel first-time-in human imaging agent, comprising the anti-PD-L1 monoclonal antibody durvalumab linked to the positron-emitting isotope 89Zr using a desferrioxamine-squaramide ester in patients with NSCLC.

Imaging PARP with [18F]rucaparib in pancreatic cancer models

PurposeRucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models.MethodWe incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models.ResultsUptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding.ConclusionTaken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.

The role of PET in imaging of the tumour microenvironment and response to immunotherapy

Positron emission tomography (PET) is an exquisitely sensitive molecular imaging technique with broad utility in cancer diagnosis and monitoring. Many ligands labelled with positron-emitting isotopes have been developed that are of interest in the field of cancer imaging. This review intends to provide an overview and outlook of PET in the field of oncology using radiotracers beyond that of the now widespread 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG). A particular focus is the role of PET in understanding and monitoring the tumour microenvironment (TME) in response to chemo-radiotherapy. Furthermore priority will be given to aspects where PET has provided for monitoring of the immune response to cancer including the expanding field of cancer immunotherapy and in the arena of theranostics. The development of new techniques from both preclinical and human studies will be included to give a perspective on future directions, thereby helping to illustrate the importance of PET in cancer patient management.

Radioactive Beams for Image-Guided Particle Therapy: The BARB Experiment at GSI.

Several techniques are under development for image-guidance in particle therapy. Positron (β+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

Copper-64-Labeled Daratumumab As a PET Imaging Tracer for Multiple Myeloma: Potential Use for Minimal Residual Disease Detection

Introduction : Minimal residual disease (MRD) is known to be an independent predictor of progression free survival (PFS) in multiple myeloma (MM). Methods of MRD detection include flow cytometry, PCR based sequencing, and imaging. However, irrespective of the sensitivity of MRD detection, techniques based on bone marrow biopsies cannot account for a “patchy,” non-homogenous bone marrow infiltration. Positron emission tomography (PET) coupled with computed tomography (CT) using 18fluoro-deoxyglucose as the radiotracer (18FDG-PET) is a commonly used imaging method that is much more sensitive than traditional radiographs, but it has several limitations; for one, lesions with a low metabolic rate may result in false negatives. Also, diffuse tracer uptake by normal marrow can obscure focal MM lesions. Daratumumab (Dara), a human anti-CD38 IgG1 (ĸ subclass) antibody against the highly expressed plasma cell receptor CD38, has been recently approved by the FDA for the treatment of MM. Based on the idea that Dara can selectively target MM cells irrespective of their metabolism, our group labeled Dara with the positron-emitting isotope copper-64 (64Cu-DOTA-Dara) in order to generate a novel imaging agent that can detect MM cells with high specificity. Our group already safely used 64Cu-labeled trastuzumab to detect HER2-positive tissue in breast cancer patients (Mortimer JE et. al. 2014), and here we provide the first pre-clinical evidence that 64Cu-labeled antibodies can be considered powerful imaging tools for MM detection.Methods :Commercially availableDara was conjugated with the NHS active ester of DOTA (Macrocyclics). DOTA-conjugated antibody was incubated with 64Cu, chased with 1 mM diethylenetriamine pentaacetic acid (DTPA), and purified on a preparative size-exclusion column. The immunoreactivity of 64Cu-DOTA-Dara was also performed using purified CD38-Fc (Chimerigen Laboratories) in an HPLC size shift assay. To assess whether 64Cu-DOTA-Dara can localize to MM cells in vivo, 5 x 106 human MM1S GFP+/Luc+ cells were injected intravenously into 6 NOD-SCID mice. At 14 days, when the bioluminescence signal in the bones of the mice were detected, mice were injected with 64Cu-DOTA-Dara (50 µCi, 10 µg), and PET imaging was performed at 21 and 44 hr after the injection (Figure 1A). Cancer free mice were used as controls (Figure 1B). 18F-FDG PET/CT scans in the same group of mice were also performed. Biodistribution studies and histological analysis were also conducted.Results : 64Cu-DOTA labeling did not affect Dara immunoreactivity against the antigen in the HPLC size shift assay. The biodistribution studies show that 64Cu-DOTA-Dara was highly detectable in the femurs, tibias, sternum and skull, known sites of MM cell invasion, which were negative in cancer-free control mice. The radionuclide was also highly detected in the lung, liver, and spleen, relative to controls. In contrast, the majority of 64Cu-DOTA-Dara remained in the blood of the control mice. Moreover, PET images show that 64Cu-DOTA-Dara PET/CT displays a higher resolution and specificity in detecting MM cells in the bones not only compared to 18F-FDG PET/CT, but even compared to bioluminescence signals from the MM cell line. To assess the specificity of 64Cu-Dara signal compared to 18F-FDG, studies using step sections in histological analysis are in process.Conclusions : Our data support the use of 64Cu-DOTA-Dara as a novel sensitive imaging agent to detect MM. The relatively short half life of 64Cu (12.7 hours) limits potential marrow toxicity and is sufficiently long for PET/CT imaging up to 48 hours after administration of the radionuclide. A pilot study assessing the safety and feasibility of 64Cu-DOTA-Dara imaging in human subjects is under way. [Display omitted] DisclosuresKeats:Amgen: Research Funding. Krishnan:Takeda: Speakers Bureau; Onyx: Speakers Bureau; Sutro: Consultancy; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Synthesis of Novel, Dual-Targeting 68Ga-NODAGA-LacN-E[c(RGDfK)]2 Glycopeptide as a PET Imaging Agent for Cancer Diagnosis.

Radiolabeled peptides possessing an Arg-Gly-Asp (RGD) motif are widely used radiopharmaceuticals for PET imaging of tumor angiogenesis due to their high affinity and selectivity to αvβ3 integrin. This receptor is overexpressed in tumor and tumor endothelial cells in the case of numerous cancer cell lines, therefore, it is an excellent biomarker for cancer diagnosis. The galectin-3 protein is also highly expressed in tumor cells and N-acetyllactosamine is a well-established ligand of this receptor. We have developed a synthetic method to prepare a lactosamine-containing radiotracer, namely 68Ga-NODAGA-LacN-E[c(RGDfK)]2, for cancer diagnosis. First, a lactosamine derivative with azido-propyl aglycone was synthetized. Then, NODAGA-NHS was attached to the amino group of this lactosamine derivative. The obtained compound was conjugated to an E[c(RGDfK)]2 peptide with a strain-promoted click reaction. We have accomplished the radiolabeling of the synthetized NODAGA-LacN-E[c(RGDfK)]2 precursor with a positron-emitting 68Ga isotope (radiochemical yield of >95%). The purification of the labeled compound with solid-phase extraction resulted in a radiochemical purity of >99%. Subsequently, the octanol–water partition coefficient (log P) of the labeled complex was determined to be −2.58. In addition, the in vitro stability of 68Ga-NODAGA-LacN-E[c(RGDfK)]2 was investigated and it was found that it was stable under the examined conditions.

Imaging and dosimetric characteristics of 67 Cu

In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67Cu (t1/2: 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64Cu (t1/2: 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67Cu, as well as producing the first report of SPECT/CT imaging using 67Cu. To this end, 67Cu was produced by photon-induced reactions on isotopically-enriched 68Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish radionuclidic purity. Absolute activity measurements corroborated manufacturer-recommended dose-calibrator settings and no radionuclidic impurities were observed. Using the Clinical Trials Network anthropomorphic chest phantom, SPECT/CT images were acquired. Medium energy (ME) SPECT collimation was found to provide the best image quality from the primary 185 keV gamma emission of 67Cu. Reconstructed images of 67Cu were similar in quality to images acquired using 177Lu. Recovery coefficients were calculated and compared against quantitative images of 99mTc, 177Lu, and 64Cu within the same anthropomorphic chest phantom. Production and clinical imaging of 67Cu appears feasible, and future studies investigating the therapeutic efficacy of 67Cu-based radiopharmaceuticals are warranted.

In vivo detection of antigen-specific CD8+ T cells by immuno-positron emission tomography.

The immune system’s ability to recognize peptides on major histocompatibility molecules (pMHCs) contributes to eradication of cancers and pathogens. Tracking these responses in vivo could help evaluate the efficacy of immune interventions and improve mechanistic understanding of immune responses. We employ synTacs, dimeric pMHC scaffolds of defined composition, which enable clonal-selective delivery of a variety of signaling, recruitment, and imaging modalities. We show that synTacs, when labeled with positron-emitting isotopes, can non-invasively image antigen-specific CD8 T cells in vivo. We imaged human papillomavirus (HPV16) E7-specific CD8 T cells by positron emission tomography with an HPV16 E7 peptide-loaded synTac in HPV16-positive tumors, following administration of a therapeutic vaccine. We also imaged influenza A virus (IAV) nucleoprotein-specific CD8 T cells in the lungs of IAV-infected mice, using an isotopically labeled flu-specific synTac. It is thus possible to visualize antigen-specific CD8 T cell populations in vivo, which may serve prognostic and diagnostic roles.

Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules.

HER3-binding affibody molecules are a promising format for visualization of HER3 expression. Cobalt-55, a positron-emitting isotope, with a half-life of 17.5 h, allows for next-day imaging. We investigated the influence of the charge of the radiocobalt–chelator complex on the biodistribution of anti-HER3 affibody molecule (HE)3-ZHER3 and compared the best radiocobalt-labeled variant with a recently optimized gallium-labeled variant. Affibody conjugates (HE)3-ZHER3-X (X = NOTA, NODAGA, DOTA, DOTAGA) were labeled with [57Co]Co (surrogate for 55Co). Affinity measurements, binding specificity and cellular processing were studied in two HER3-expressing cancer cell lines. Biodistribution was studied 3 and 24 h post-injection (pi) in mice with HER3-expressing BxPC-3 xenografts and compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA. Micro-single-photon emission tomography/computed tomography (microSPECT/CT) and micro-positron emission tomography/computed tomography (microPET/CT) imaging was performed 3 and 24 h pi. Stably labeled conjugates bound to HER3 with subnanomolar affinity. [57Co]Co-(HE)3-ZHER3-DOTA had the best tumor retention and a significantly lower concentration in blood than other conjugates, leading to superior tumor-to-blood and tumor-to-liver ratios 24 h pi. Compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA 3 h pi, [57Co]Co-(HE)3-ZHER3-DOTA provided superior imaging contrast in liver 24 h pi. Concluding, the composition and charge of the [57Co]Co–chelator complex influenced the uptake in tumors and normal tissue. [57Co]Co-(HE)3-ZHER3-DOTA provided the best imaging properties among the cobalt-labeled conjugates. Delayed imaging of HER3 expression with [57Co]Co-(HE)3-ZHER3-DOTA improved imaging contrast compared to early-time-point imaging with [68Ga]Ga-(HE)3-ZHER3-NODAGA.

18F-fluoride as a prognostic indicator of bone regeneration

Positron emission tomography (PET) is a form of nuclear imaging, which quantitatively assesses the metabolic activity through the uptake of radioactive tracers. 18F-fluoride is a positron-emitting isotope with high affinity for bone. Despite its potential as a non-invasive measure of bone metabolism, quantitative 18F-fluoride PET has only been used sparsely in orthopaedic applications. It has been speculated that 18F-fluoride PET characterizes cellular activity of bone forming cells in the early stages of the regenerative process and therefore precedes the mineralization detected by conventional computed tomography (CT). Our aim was thus to combine in vivo PET and CT to map the spatiotemporal course of bone regeneration during fracture healing using an open femur fracture model in the rat and characterize regeneration in untreated and pharmacologically treated fractures using both imaging modalities. We hypothesized that PET 18F-fluoride tracer activity at an earlier time point is predictive of CT measured bone formation at a later time point. On the basis of the RMSE and R2 metrics of linear regression models it was conceivable for bone volumes to be predicted up to three weeks in advance in a rodent model (RMSE: 14 mm3–18 mm3, R2: 0.79–0.82). Moreover, the data suggested that 18F-fluoride positron-emitting activity had the potential to separate bone formation from resorption and thus could be of interest across a wide array of orthopaedic applications. Based on this data, we conclude that 18F-fluoride positron-emitting activity is strongly correlated to bone formation and could potentially predict the volume of bone regenerated at fracture sites. The volume of bone regenerated at a fracture site can be interpreted as a measure of the healing response and 18F-fluoride should be further investigated as a predictive diagnostic tool to identify if bone fractures will heal successfully or result in delayed healing or non-union. Statement of SignificanceWe aimed to combine in vivo PET and CT imaging to map the spatiotemporal course of bone regeneration during fracture healing using an open femur fracture model in the rat and characterize regeneration in untreated and pharmacologically treated fractures using both imaging modalities. We hypothesized that PET 18F-fluoride tracer activity at an earlier time point is predictive of CT measured bone formation at a later time point.Our data suggest that 18F-fluoride positron-emitting activity can separate bone formation from resorption and thus could be of interest across a wide array of orthopaedic applications including as a predictive diagnostic tool to identify if fractures will heal successfully or result in delayed healing or non-union.

The application of positron emission tomography (PET) imaging in CNS drug development.

As drug discovery and development in Neuroscience push beyond symptom management to disease modification, neuroimaging becomes a key area of translational research that enables measurements of the presence of drugs and downstream physiological consequences of drug action within the living brain. As such, neuroimaging can be used to help optimize decision-making processes throughout the various phases of drug development. Positron Emission Tomography (PET) is a functional imaging technique that allows the quantification and visualization of biochemical processes, by monitoring the time dependent distribution of molecules labelled with short-lived positron-emitting isotopes. This review focuses on the application of PET to support CNS drug development, particularly in the early clinical phases, by allowing us to measure tissue exposure, target engagement, and pharmacological activity. We will also discuss the application of PET imaging as tools to image the pathological hallmarks of disease and evaluate the potential disease-modifying effect of candidate drugs in slowing disease progression.

A positron emission tomography image-guidable unimolecular micelle nanoplatform for cancer theranostic applications

Unimolecular micelles based on hyperbranched polyamidoamine (PAMAM) dendrimer were synthesized as both a cargo delivery vector and an imaging agent for triple-negative breast tumors, and the chemical synthesis procedures are detailed in this study. With the chemical conjugation of a peptide (F3, against cellular nucleolin) to increase its cellular internalization, these micelles can accumulate potently and specifically in breast cancer cells (e.g., MDA-MB-231). The size and morphology of these PAMAM-based micelles have been measured by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The hydrazone bond (responsive to pH alteration) between the loaded doxorubicin (DOX, as a model drug here) and PAMAM micelles enables cargo release following pH changes. Flow cytometry and confocal fluorescence microscopy revealed that PAMAM micelles with F3 attachment (PAMAM-DOX-F3) had stronger internalization into MDA-MB-231 cells (nucleolin-positive) than PAMAM micelles without F3 conjugation (PAMAM-DOX), whereas both of them have minimal interactions with L929 fibroblasts (nucleolin-negative). The positron-emitting isotope 64Cu was added into PAMAM micelles by chelation to track their pharmacokinetic behavior (organ distribution profile) in vivo by positron emission tomography (PET) imaging. Serial PET imaging demonstrated that the accumulation of 64Cu-PAMAM-DOX-F3 in MDA-MB-231 tumors was fast, potent, and persistent (tumor uptake: 6.1 ± 1.2% injection dose per gram [%ID/g] at 24 h p.i.), significantly higher than that of 64Cu-PAMAM-DOX (2.5 ± 0.4%ID/g at the same time). Their distribution profiles in other organs/tissues were quite similar, with a relatively short circulation time. In addition, ex vivo fluorescence imaging confirmed that DOX can be delivered efficiently by these PAMAM micelles to MDA-MB-231 tumors. Deducing from these data, we believe that PAMAM-based micelles can be useful for selective combinational treatment of cancer. Statement of SignificanceMicelles are a very useful biomaterial for theranostic purposes, and one of the major hurdles for micelles (particularly those from self-assembling) is their relatively low stability, especially when administered in vivo. In this study, we have attempted to overcome this limitation by designing unimolecular micelles (based on the concept of “one micelle is composed of one macromolecule”) from polyamidoamine (PAMAM) dendrimers, in which the drug cargos (e.g., doxorubicin) are chemically attached to PAMAM through a hydrazone bond; hence, they can be used as a tumor-selective diagnostic/therapeutic platform. These unimolecular micelles possess superior stability compared to conventional micelles and can undertake stimulus (pH)-responsive cargo release for more “targeted” cancer therapy. With the incorporation of a tumor-targeting peptide sequence (F3) and a positron-emitting isotope (copper-64), the pharmacokinetic behavior of these micelles can be readily monitored by positron emission tomography imaging technique to confirm their specificity against cancer tissues. With further optimization, this micellar platform can have a broad clinical applicability owing to its biocompatibility, selectivity, and stability.

Design considerations for a pulse line ion accelerator (PLIA)-based PET isotope generator.

Positron emission tomography (PET) imaging remains limited due to the cost associated with on-site production of short half-life, positron-emitting isotopes. In this work, we examine the use of a pulse line ion accelerator (PLIA) to accelerate protons for single-dose PET isotope production. Time-domain electromagnetic field and particle-in-cell (PIC) simulations were performed for a 1.5-m PLIA structure modeled in CST Microwave Studio and Particle Studio software. Scaled measurements from a kV ramp-pulse generator were incorporated into the simulations to accelerate a 1 A, 50 ns proton beam injected with initial kinetic energy of 100 keV. A uniform, 3 T, solenoidal magnetic field was used to provide external beam focusing. Electromagnetic fields and particle phase space were recorded with ns resolution for subsequent analysis. Applying a scaled 100 kV, 20 ns ramped voltage pulse to the PLIA input resulted in a travelling electric field wave inside the structure with accelerating gradient of 2.4 MV/m. The observed wave speed was 1.2 × 107 m/s and is in good agreement with theoretical predictions. Phase space monitors showed both acceleration and bunching of the proton beam, with a maximum kinetic energy of 2.5 MeV, observed at the exit of the single PLIA stage. Evaluation of beam position monitors at different locations in the accelerator showed bunch compression and minimal beam divergence, illustrating that the 3 T field is adequate to contain the beam over the length of the PLIA structure. Simulations performed in this work demonstrate the feasibility of using a PLIA structure to accelerate protons with MV/m level gradients. Combining several PLIA stages in series could allow for a low-cost accelerator suitable for dose-on-demand PET isotope production.

Insights into Trace Metal Metabolism in Health and Disease from PET: "PET Metallomics".

Essential trace metals such as copper, zinc, iron, and manganese perform critical functions in cellular and physiologic processes including catalytic, regulatory, and signaling roles. Disturbed metal homeostasis is associated with the pathogenesis of diseases such as dementia, cancer, and inherited metabolic abnormalities. Intracellular pathways involving essential metals have been extensively studied but whole-body fluxes and transport between different compartments remain poorly understood. The growing availability of PET scanners and positron-emitting isotopes of key essential metals, particularly 64Cu, 63Zn, and 52Mn, provide new tools with which to study these processes in vivo. This review highlights opportunities that now present themselves, exemplified by studies of copper metabolism that are in the vanguard of a new research front in molecular imaging: “PET metallomics.”