Positron Emission Tomography Agents Research Articles

In vivo assessment of safety, biodistribution, and radiation dosimetry of the [18F]Me4FDG PET-radiotracer in adults

BackgroundApproaches targeting the sodium-glucose cotransporter (SGLT) could represent a promising future therapeutic strategy for numerous oncological and metabolic diseases. In this study, we evaluated the safety, biodistribution and radiation dosimetry of the glucose analogue positron emission tomography (PET) agent [18F] labeled alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) with high sodium-glucose cotransporter and low glucose transporter (GLUT) affinity. For this purpose, five healthy volunteers (1 man, 4 women) underwent multiple whole-body PET/computed tomography (CT) examinations starting with injection and up to 4 h after injection of averaged (2.4 ± 0.1) MBq/kg (range: 2.3–2.5 MBq/kg) administered activity. The PET/CT scans were conducted in 5 separate sessions, blood pressure and temperature were measured, and blood and urine samples were collected before the scans and one hour after injection to assess toxicity. Measurements of [18F]Me4FDG radioactivity in organs of interest were determined from the PET/CT scans at 5 time points. Internal dosimetry was performed on voxel level using a fast Monte Carlo approach.ResultsAll studied volunteers could well tolerate the [18F]Me4FDG and no adverse event was reported. The calculated effective dose was (0.013 ± 0.003) mSv/MBq. The organs with the highest absorbed dose were the kidneys with 0.05 mSv/MBq per kidney. The brain showed almost no uptake. After 60 min, (12 ± 15) % of the administered dose was excreted into the bladder.ConclusionFeaturing an effective dose of only 0.013 ± 0.003 mSv/MBq and no occurrence of side effects, the glucose analogue [18F]Me4FDG seems to be a safe radio-tracer with a favorable biodistribution for PET imaging and also within several consecutive scans.Trial registration numberNCT03557138, Registered 22 February 2017, https://ichgcp.net/clinical-trials-registry/NCT03557138.

Developing Low Molecular Weight PET and SPECT Imaging Agents.

Imaging agents for positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) have shown their utility in many situations, answering clinical questions related to drug development and medical considerations. The discovery and development of imaging agents follow a well-understood process, with variations related to available starting points and to the envisaged imaging application. This article describes the general development path leading from the expression of an imaging need and project initiation to a clinically usable imaging agent. The definition of the project rationale, the design and optimization of early leads, and the assessment of the imaging potential of an imaging agent candidate are followed by preclinical and clinical development activities that differ from those required for therapeutic agents. These include radiolabeling with a positron emitter and first-in-human clinical studies, to rapidly evaluate the ability of a new imaging agent to address the questions it was designed to answer.

Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [55Co]Co-NT-Sarcage as a Proof of Concept in a Murine Xenograft Model.

Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added 55Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with 55Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [55Co]CoCl2 to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [55Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice. The [55Co]Co-DSar complex can be formed at 37 °C with purity and stability suitable for preclinical in vivo radiopharmaceutical applications, and [55Co]Co-NT-Sarcage demonstrated prominent tumor uptake with a low background signal. In a direct comparison with [64Cu]Cu-NT-Sarcage, [55Co]Co-NT-Sarcage achieved a higher tumor-to-liver ratio but with overall similar biodistribution profile. These results demonstrate that Sar would be a promising chelator for constructing Co-based radiopharmaceuticals including 55Co for PET and 58mCo for therapeutic applications.

Accuracy of Injection Dose of Amyloid PET Agent Using Radiopharmaceutical Activity Suppliers

This study aimed to identify disposable items with low amyloid positron emission tomography (PET) agent radioactivity adsorption for accurate injections using a radiopharmaceutical activity supplier. First, we investigated disposable items currently used for amyloid PET agent injection. Next, we measured the residual radioactivity rates of amyloid PET agents on three-way stopcocks, extension tubes, butterfly needles, and indwelling needles to identify disposable items with low radioactivity adsorption. Finally, we evaluated the accuracy of amyloid PET agent injection using the selected disposable items and a radiopharmaceutical activity supplier. The polybutadiene extension tube exhibited a significantly lower residual activity rate than that of the polyvinyl chloride extension tube. Similarly, the indwelling needles showed significantly lower residual activity rate than that of butterfly needles. The dose indicated by a radiopharmaceutical activity supplier was 184.1 MBq, while the dose calibrator measured the radioactivity which flowed into the vial as 170.2 MBq, resulting in an administration accuracy of 8.2%. To ensure accurate amyloid PET agent injections, we recommend using polybutadiene extension tubes and indwelling needles due to their lower radioactivity adsorption.

Photocatalyzed radiosynthesis of 11C-phenylacetic acids.

Fast and straightforward incorporation of radionuclides into pharmaceutically relevant molecules is one of the main barriers to preclinical and clinical tracer research. Late-stage direct incorporation of cyclotron-produced [11C]CO2 to afford carbon-11-labeled radiopharmaceuticals has the potential to provide ready-to-inject positron emission tomography agents in less than an hour. The present work describes photocatalyzed carboxylation of alkylbenzene derivatives to afford 11C-phenylacetic acids. Reaction conditions and scope are investigated followed by application of this methodology to the preparative radiosynthesis of [11C]fenoprofen, a nonsteroidal anti-inflammatory drug.

Molecular Imaging of Infections: Emerging Techniques for Pathogen-Specific Diagnosis and Guided Therapy.

Evaluation of patients that may be infected is challenging. Imaging to identify or localize a site of infection is often limited because of the nonspecific nature of the findings on conventional imaging modalities. Available imaging methods lack the ability to determine if antibiotics are reaching the site of infection and are not optimized to follow response to therapy. Positron emission tomography (PET) is a method by which radiolabeled molecules can be used to detect metabolic perturbations or levels of expression of specific targets. The most common PET agent is the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). 18F-FDG has some applicability to localizing a site of infection, but its lack of specificity limits its usefulness. There is a need for the development of pathogen-specific PET radiotracers to address the imaging shortcomings noted above. Preclinical and clinical progress has been made, but significant challenges remain.

Copper(II) Complexes of 2,2'-Bisdipyrrins: Synthesis, Characterization, Cell Uptake, and Radiolabeling with Copper-64.

Complexes prepared with positron-emitting copper-64 are of interest as imaging agents for positron emission tomography (PET). This work investigates the potential of using acyclic tetrapyrrolic 2,2'-bisdipyrrins as ligands to prepare charge-neutral, lipophilic, cell-permeable, redox active complexes with positron-emitting copper-64. The synthesis and characterization of a series of tetrapyrrolic 2,2'-bisdipyrrin copper(II) complexes are reported. Four 2,2'-bisdipyrrin copper(II) complexes were prepared with different functional groups in the meso-position of the ligands. Two of the new copper(II) complexes, one palladium(II) complex, and one nickel(II) complex were characterized by X-ray crystallography, which demonstrated that the copper(II) is in a distorted square planar environment. An investigation of the electrochemical properties of the complexes by cyclic voltammetry revealed that the complexes undergo multiple quasi-reversible processes. A comparison of the cyclic voltammetry of the copper complexes with their palladium(II) analogues suggests that these redox processes are ligand-based and not metal-based. The copper(II) complexes are cell-permeable in A431 mammalian cells and are nontoxic at concentrations of 50 μM. The ligands can be radiolabeled with copper-64 at room temperature.

Stereotactic Body Radiation Therapy Salvage for Lymph Node Recurrent Prostate Cancer in the Era of PSMA PET Imaging.

Our understanding of patterns of prostate cancer recurrence after primary treatment of localized disease has significantly evolved since the development of positron emission tomography (PET) agents targeting prostate cancer. Previously, most biochemical recurrences were not associated with imaging correlates when restaging with computed tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy and, hence, were typically assumed to represent occult metastases. A rising prostate specific antigen (PSA) after previous local therapy prompting a PET scan showing uptake limited to regional lymph nodes is an increasingly common clinical scenario as advanced prostate cancer imaging becomes more widely utilized. The optimal management strategy for patients who have lymph node recurrent prostate cancer is both unclear and evolving, particularly in terms of local and regionally directed therapies. Stereotactic body radiation therapy (SBRT) utilizes ablative radiation doses with steep gradients to achieve local tumor control while sparing nearby normal tissues. SBRT is an attractive therapeutic modality due to its efficacy, favorable toxicity profile, and flexibility to administer elective doses to areas of potential occult involvement. The purpose of this review is to briefly describe how SBRT is being implemented in the era of PSMA PET for the management of solely lymph node recurrent prostate cancer. SBRT has been shown to effectively control individual lymph node tumor deposits within the pelvis and retroperitoneum for prostate cancer and is well-tolerated with a favorable toxicity profile. However, a major limitation thus far has been the lack of prospective trials supporting the use of SBRT for oligometastatic nodal recurrent prostate cancer. As further trials are conducted, its exact role in the treatment paradigm of recurrent prostate cancer will be better established. Although PET-guided SBRT appears feasible and potentially beneficial, there is still considerable uncertainty about the use of elective nodal radiotherapy (ENRT) in patients with nodal recurrent oligometastatic prostate cancer. PSMA PET has undoubtedly advanced imaging of recurrent prostate cancer, revealing anatomic correlates for disease recurrence that previously went undetected. At the same time, SBRT continues to be explored in prostate cancer with feasibility, a favorable risk profile, and satisfactory oncologic outcomes. However, much of the existing literature comes from the pre-PSMA PET era and integration of this novel imaging approach has led to greater focus on new and ongoing clinical trials to rigorously evaluate this approach and compare to other established treatment modalities utilized for oligometastatic, nodal recurrence of prostate cancer.

Exploration of Imaging Biomarkers for Metabolically-Targeted Osteosarcoma Therapy in a Murine Xenograft Model.

Background: Osteosarcoma (OS) is an aggressive pediatric cancer with unmet therapeutic needs. Glutaminase 1 (GLS1) inhibition, alone and in combination with metformin, disrupts the bioenergetic demands of tumor progression and metastasis, showing promise for clinical translation. Materials and Methods: Three positron emission tomography (PET) clinical imaging agents, [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG), 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), and (2S, 4R)-4-[18F]fluoroglutamine ([18F]GLN), were evaluated in the MG63.3 human OS xenograft mouse model, as companion imaging biomarkers after treatment for 7 d with a selective GLS1 inhibitor (CB-839, telaglenastat) and metformin, alone and in combination. Imaging and biodistribution data were collected from tumors and reference tissues before and after treatment. Results: Drug treatment altered tumor uptake of all three PET agents. Relative [18F]FDG uptake decreased significantly after telaglenastat treatment, but not within control and metformin-only groups. [18F]FLT tumor uptake appears to be negatively affected by tumor size. Evidence of a flare effect was seen with [18F]FLT imaging after treatment. Telaglenastat had a broad influence on [18F]GLN uptake in tumor and normal tissues. Conclusions: Image-based tumor volume quantification is recommended for this paratibial tumor model. The performance of [18F]FLT and [18F]GLN was affected by tumor size. [18F]FDG may be useful in detecting telaglenastat's impact on glycolysis. Exploration of kinetic tracer uptake protocols is needed to define clinically relevant patterns of [18F]GLN uptake in patients receiving telaglenastat.

Ultrasmall, elementary and highly translational nanoparticle X-ray contrast media from amphiphilic iodinated statistical copolymers.

To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity, and well-defined spatial and temporal resolutions, a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media (nano-XRCM) as dual-modality imaging agents for positron emission tomography (PET) and computed tomography (CT) has been established. Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide) acrylate monomers, the amphiphilic statistical iodocopolymers (ICPs) could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations (>140mg iodine/mL water) and comparable viscosities to conventional small molecule XRCM. The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca. 10nm in water was confirmed by dynamic and static light scattering techniques. In a breast cancer mouse model, invivo biodistribution studies revealed that the 64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents. PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals, while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection, enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.

Development of [18F]F-5-OMe-Tryptophans through Photoredox Radiofluorination: A New Method to Access Tryptophan-Based PET Agents.

Although various radiolabeled tryptophan analogs have been developed to monitor tryptophan metabolism using positron emission tomography (PET) for various human diseases including melanoma and other cancers, their application can be limited due to the complicated synthesis process. In this study, we demonstrated that photoredox radiofluorination represents a simple method to access novel tryptophan-based PET agents. In brief, 4-F-5-OMe-tryptophans (l/d-T13) and 6-F-5-OMe-tryptophans (l/d-T18) were easily synthesized. The 18F-labeled analogs were produced by photoredox radiofluorination with radiochemical yields ranging from 2.6 ± 0.5% to 32.4 ± 4.1% (3 ≤ n ≤ 5, enantiomeric excess ≥ 99.0%) and over 98.0% radiochemical purity. Small animal imaging showed that l-[18F]T13 achieved 9.58 ± 0.26%ID/g tumor uptake and good contrast in B16F10 tumor-bearing mice (n = 3). Clearly, l-[18F]T13 exhibited prominent tumor uptake, warranting future evaluations of its potential usage in precise immunotherapy monitoring.

Design, Synthesis, and Biological Evaluation of a Small-Molecule PET Agent for Imaging PD-L1 Expression.

Immunotherapy blocking programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) pathway has achieved great therapeutic effect in the clinic, but the overall response rate is not satisfactory. Early studies showed that response to treatment and overall survival could be positively related to PD-L1 expression in tumors. Therefore, accurate measurement of PD-L1 expression will help to screen cancer patients and improve the overall response rate. A small molecular positron emission tomography (PET) probe [18F]LP-F containing a biphenyl moiety was designed and synthesized for measurement of PD-L1 expression in tumors. The PET probe [18F]LP-F was obtained with a radiochemical yield of 12.72 ± 1.98%, a radiochemical purity of above 98% and molar activity of 18.8 GBq/μmol. [18F]LP-F had good stability in phosphate buffer saline (PBS) and mouse serum. In vitro assay indicated that [18F]LP-F showed moderate affinity to PD-L1. Micro-PET results showed that the tumor accumulation of [18F]LP-F in A375 tumor was inferior to that in A375-hPD-L1 tumor. All the results demonstrated that [18F]LP-F could specifically bind to PD-L1 and had a potential application in non-invasive evaluation of PD-L1 expression in tumors.

11C-, 12C-, and 13C-cyanation of electron-rich arenes via organic photoredox catalysis

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

Evaluation of sulfone-labeled amino acid derivatives as potential PET agents for cancer imaging

IntroductionAs one of the most important and frequently used molecular imaging techniques in the clinic, positron emission tomography (PET) features high sensitivity and specificity, which generally involves the use of PET contrast agents. Despite the exceptional promise, the availability of novel PET agents could limit its application and there is a clear need to develop new PET agents to improve our understanding of targets of interest and increase the diagnostic specificity. MethodsBased on the fact that amino acid transport and protein anabolism are increased in tumor tissues, a series of 18F-labeled amino acid analog was labeled with 18F by using [18F]fluoro-4-(vinylsulfonyl)benzene as the radionuclide linker. The obtained probes were subjected to in vitro and in vivo evaluation, including stability, cell line transport channel specificity, PET/CT imaging on tumor and inflammation bearing mice, and biodistribution. ResultsOur data shows that [18F]2a had moderate decay corrected labeling yield (>42 %) and high radiochemical purity (>99 %). When tested in vivo, the uptake of [18F]2a was 1.5 ± 0.2%ID/g in NCI-H1975 tumors and 1.1 ± 0.2%ID/g in inflammatory tissues. In contrast, the values for [18F]FDG were 5.7 ± 0.2%ID/g and 4.8 ± 0.1%ID/g, respectively. The inflammatory lesion-to-muscle contrast is 2.4 for [18F]2a, which is 3.0 for [18F]FDG. ConclusionClearly, [18F]2a hold the great potential for cancer imaging. Its application in distinguishing tumor from inflammatory lesion would still need to be investigated further.

Development and evaluation of an 18F-labeled nanobody to target SARS-CoV-2's spike protein

COVID-19, caused by the SARS-CoV-2 virus, has become a global pandemic that is still present after more than two years. COVID-19 is mainly known as a respiratory disease that can cause long-term consequences referred to as long COVID. Molecular imaging of SARS-CoV-2 in COVID-19 patients would be a powerful tool for studying the pathological mechanisms and viral load in different organs, providing insights into the disease and the origin of long-term consequences and assessing the effectiveness of potential COVID-19 treatments. Current diagnostic methods used in the clinic do not allow direct imaging of SARS-CoV-2. In this work, a nanobody (NB) – a small, engineered protein derived from alpacas – and an Fc-fused NB which selectively target the SARS-CoV-2 Spike protein were developed as imaging agents for positron emission tomography (PET). We used the tetrazine ligation to 18F-label the NB under mild conditions once the NBs were successfully modified with trans-cyclooctenes (TCOs). We confirmed binding to the Spike protein by SDS-PAGE. Dynamic PET scans in rats showed excretion through the liver for both constructs. Future work will evaluate in vivo binding to the Spike protein with our radioligands.

Modular PET Agent Construction Strategy through Strain-Promoted Double-Click Reagent with Efficient Photoclick Step.

An efficient modular strategy for rapid assembly of positron emission tomography (PET) agents has been developed. The use of a sequential, rapid, and selective double-click reaction allows for a combinatorial approach to the cross-linking of positron emitter-bearing prosthetic groups with various ligands. The strain-promoted azide alkyne cyclization (SPAAC) coupling of 18F-labeled azide synthon with MC-DIBOD, a cyclooctadiyne with one of the triple bonds caged as a cyclopropenone moiety, produces a stable intermediate. A brief exposure of the latter to 350-420 nm light removes protection of the second triple bond allowing for the addition of an azide-tagged biomolecule. The utility of this strategy has been demonstrated by the construction of several PET agents. The value of modularity was demonstrated in the preparation of PSMA PET agents, where the hydrophilicity was easily modified to improve tumor to background contrast.

A practical approach to the optimization of positron emission tomography imaging agents for the central nervous system

The discovery of novel imaging agents for positron emission tomography (PET) relies on medicinal chemistry best practices, including a good understanding of molecular and pharmacological properties required for the acquisition of relevant, high-quality images. This short note reviews the characteristics of a series of clinically successful imaging agents, providing guidance for the optimization of such molecular tools. PET imaging plays an important role in staging disease and in helping clinical dose selection, which is critical for the efficient development of drug candidates.

Piflufolastat F-18 (18F-DCFPyL) for PSMA PET imaging in prostate cancer

Introduction Accurate imaging is essential for staging prostate cancer and guiding management decisions. Conventional imaging modalities are hampered by a limited sensitivity for metastatic disease. Nearly all prostate cancers express prostate-specific membrane antigen (PSMA) and 18F-DCFPyL (piflufolastat F 18) is a new FDA-approved positron emission tomography (PET) agent that targets PSMA for improved staging of prostate cancer. Areas covered This article provides an overview of PSMA, the mechanism of action of 18F-DCFPyL, and compares the performance of 18F-DCFPyL to conventional prostate imaging modalities. Current prostate cancer imaging guidelines are reviewed, as well as what changes can be expected in the future with increased access to PSMA-PET. Expert opinion The OSPREY and CONDOR clinical trials have demonstrated the superiority of 18F-DCFPyL over conventional imaging modalities for the staging and restaging of prostate cancer. The remarkable diagnostic accuracy of PSMA-PET is reshaping prostate cancer imaging and the modularity of these agents hint at exciting new diagnostic and therapeutic opportunities that have the potential to improve the care of patients with prostate cancer as a whole.

PSMA theragnostics for metastatic castration resistant prostate cancer

There has been tremendous growth in the development of theragnostics for personalized cancer diagnosis and treatment over the past two decades. In prostate cancer, the new generation of prostate specific membrane antigen (PSMA) small molecular inhibitor-based imaging agents achieve extraordinary tumor to background ratios and allow their therapeutic counterparts to deliver effective tumor doses while minimizing normal tissue toxicity. The PSMA targeted small molecule positron emission tomography (PET) agents 18F-DCFPyL (2-(3-{1-carboxy-5-((6-(18)F-fluoro-pyridine-3-carbonyl)-amino)-pentyl}-ureido)-pentanedioic acid) and Gallium-68 (68Ga)-PSMA-11 have been approved by the United States Food and Drug Administration (FDA) for newly diagnosed high risk prostate cancer patients and for patients with biochemical recurrence. More recently, the Phase III VISION trial showed that Lutetium-177 (177Lu)-PSMA-617 treatment increases progression-free survival and overall survival in patients with heavily pre-treated advanced PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we review the PSMA targeted theragnostic pairs under clinical investigation for detection and treatment of metastatic prostate cancer.

Synthesis and Evaluation of 18F-Labeled Boramino Acids as Potential New Positron Emission Tomography Agents for Cancer Management.

Boron neutron capture therapy (BNCT) is a promising cancer treatment strategy that utilizes boron-containing ligands. In this report, a series of substituted boramino acids were synthesized and evaluated, aiming to obtain metabolically stable boron-derived agents that could integrate positron emission tomography (PET) with BNCT (a theranostic agent). Based on the phenylalanine (Phe) core structure, the impact of substitution groups on tumor accumulation was studied. The agents were labeled with fluorine-18 in 27.2-66.8% yield via the 18F-19F isotope exchange reaction. In B16-F10 tumor-bearing mice, [18F]-(R)-(1-ammonio-2-(4-methoxyphenyl) ethyl) trifluoroborate (R-[18F]-5a) demonstrated the best tumor uptake (5.54 ± 2.32% ID/g based on ex vivo biodistribution and 3.5 ± 0.04% ID/g based on PET imaging with the tumor-to-muscle ratio up to 2.6) and stability compared with other tested agents. Together, R-[18F]-5a is a promising agent that could potentially integrate PET and BNCT, whose treatment efficacy is worth further evaluation in the future.