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Abstract Background Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically “hot” tumors. However, immune dynamics in the low T-cell infiltrating “cold” tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response. Methods [89Zr]Zr-DFO-CD4 and [89Zr]Zr-DFO-CD8 radiotracers were used to quantify changes in intratumoral and splenic CD4 T cells and CD8 T cells in response to ICB treatment in 4T1 and MMTV-HER2 mouse models, which represent immunologically “cold” tumors. A correlation between PET quantification metrics and long-term anti-tumor response was observed. Further biological validation was obtained by autoradiography and immunofluorescence. Results Following ICB treatment, an increase in the CD8-specific PET signal was observed within 6 days, and an increase in the CD4-specific PET signal was observed within 2 days in tumors that eventually responded to immunotherapy, while no significant differences in CD4 or CD8 were found at the baseline of treatment that differentiated responders from nonresponders. Furthermore, mice whose tumors responded to ICB had a lower CD8 PET signal in the spleen and a higher CD4 PET signal in the spleen compared to non-responders. Intratumoral spatial heterogeneity of the CD8 and CD4-specific PET signals was lower in responders compared to non-responders. Finally, PET imaging, autoradiography, and immunofluorescence signals were correlated when comparing in vivo imaging to ex vivo validations. Conclusions CD4- and CD8-specific immuno-PET imaging can be used to characterize the in vivo distribution of CD4 + and CD8 + T cells in response to immune checkpoint blockade. Imaging metrics that describe the overall levels and distribution of CD8 + T cells and CD4 + T cells can provide insight into immunological alterations, predict biomarkers of response to immunotherapy, and guide clinical decision-making in those tumors where the kinetics of the response differ.

Abstract Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([89Zr]-panitumumab and [89Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastuzumab, cetuximab, or combination followed by radiation to assess for viability and radiosensitivity (colony forming assay, immunofluorescence, and flow cytometry). In vivo, [18F]-FMISO-PET imaging was used to quantify changes in oxygenation during treatment. Bliss Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a 50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases in DNA damage response and increased response to radiation therapy (p

Abstract The radioscandium isotopes, 43Sc and 47Sc, compose a promising elementally matched theranostic pair that can be used for the development of imaging and therapeutic radiopharmaceuticals with identical structures. This study aimed to investigate the production of high radionuclidic purity 43Sc from enriched [46Ti]TiO2 targets and 47Sc from enriched [50Ti]TiO2 targets and establish a target recycling technique. Enriched [46Ti]TiO2 targets were irradiated with 18 MeV protons, and enriched [50Ti]TiO2 targets were bombarded with 24 MeV protons. 43Sc and 47Sc were purified using ion chromatography attaining recovery yields of 91.7 ± 7.4% and 89.9 ± 3.9%, respectively. The average radionuclidic purity for 43Sc was 98.8 ± 0.3% and for 47Sc 91.5 ± 0.6%, while the average recovery of enriched titanium target material was 96 ± 4.0%. The highest apparent molar activity for [43Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [47Sc]Sc-DOTA. This work demonstrates the feasibility of using enriched recycled [46Ti]TiO2 and [50Ti]TiO2 targets to produce high purity 43Sc and 47Sc as an elementally matched theranostic isotope pair.

Abstract The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16–21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023. Over 360 abstracts were presented from all over the world by a diverse group of global scientists working with radiopharmaceuticals. Given this group of international radiochemists is unique to ISTR (IAEA funding enabled many to attend), there was an invaluable wealth of knowledge on the global state of the radiopharmaceutical sciences present at the meeting. The intent of this Proceedings paper is to share this snapshot from our international colleagues with the broader radiopharmaceutical sciences community by highlighting presentations from the conference on the following topics: Isotope Production and Radiochemistry, Industrial Insights, Regional Trends, Training and Education, Women in the Radiopharmaceutical Sciences, and Future Perspectives and New Initiatives. The authors of this paper are employees of IAEA, members of the ISTR-2023 Organizing Committee and/or members of the EJNMMI Radiopharmacy and Chemistry Editorial Board who attended ISTR-2023. Overall, ISTR-2023 fostered the successful exchange of scientific ideas around every aspect of the radiopharmaceutical sciences. It was well attended by a diverse mix of radiopharmaceutical scientists from all over the world, and the oral and poster presentations provided a valuable update on the current state-of-the-art of the field amongst IAEA Member States. Presentations as well as networking amongst the attendees resulted in extensive knowledge transfer amongst the various stakeholders representing 88 IAEA Member States. This was considered particularly valuable for attendees from Member States where nuclear medicine and the radiopharmaceutical sciences are still relatively new. Since the goal is for the symposium series to be held every four years; the next one is anticipated to take place in 2027.

Molecular imaging is an important part of modern medicine which enables the non-invasive identification and characterization of diseases. With the advancement of radiochemistry and scanner technology, nuclear medicine is providing insight into efficient treatment options for individual patients. Titanium-45 (45Ti) is a lesser-explored radionuclide that is garnering increasing interest for the development of positron emission tomography (PET) radiopharmaceuticals. This review discusses aspects of this radionuclide including production, purification, radiochemistry development, and molecular imaging studies.

OBJECTIVES/GOALS: This study was performed to explore the capabilities of simultaneous [89 Zr]trastuzumab-PET/MRI acquisition in a cohort of metastatic HER2+ breast cancer. The insights derived provide additional noninvasive characterization and precise intratumoral analysis tools for healthcare providers. METHODS/STUDY POPULATION: A total of 13 patients, aged between 40 and 70, diagnosed with HER2-positive breast cancer, were selected to participate in this study. Whole-body [89 Zr]trastuzumab-PET/MR imaging was performed 5 ± 1 days post-injection of the radiopharmaceutical during ongoing HER2-directed therapy. Concurrently acquired T1-weighted MRI facilitated the identification of normal organ and tumor regions of interest, which were further analyzed for mean ADC and mean standardized uptake value. Multiparametric intratumoral habitat analysis was performed. Utilizing the median metric values, tumors were evaluated for heterogeneity, specifically assessing high and low HER2 expression through an image processing framework in conjunction with ADC metrics. Long-term treatment response evaluation is ongoing. RESULTS/ANTICIPATED RESULTS: Initial analysis indicate all tumors exhibited higher overall uptake of [89 Zr]trastuzumab across various sites including the bone (p=0.019), brain (p=0.014), and breast (p=0.069), when compared to corresponding normal organs. Additionally, increased ADCmean values were observed in all regions besides brain tumors (bone: p=0.002, brain: p=0.5, breast: p=0.03, juxtapulmonary: p=0.037), indicating distinct patterns of cellularity. Notably, one of five patients with a breast lesion, who exhibited a complete response to HER2-targeted therapy, exhibited the highest breast lesion SUVmean. Brain and lymph node lesions demonstrated intratumoral heterogeneity of HER2 expression. Qualification of multi parametric maps is anticipated to inform on intratumoral heterogeneity DISCUSSION/SIGNIFICANCE: Despite limitation in clinical applications of quantitative approaches due to lack of standardization of processing, initial investigations, in combining molecular imaging of HER2 and quantitative MRI demonstrate potential in characterizing metastatic HER2+ breast cancer for intratumoral classification and therapeutic stratification.

Abstract 52Mn is a promising PET radiometal with a half-life of 5.6 days and an average positron energy of 242 keV. Typically, chromium of natural isotope abundance is used as a target material to produce this isotope through the nat/52Cr(p,n)52Mn reaction. While natural Cr is a suitable target material, higher purity 52Mn could be produced by transitioning to enriched 52Cr targets to prevent the co-production of long-lived 54Mn (t1/2 = 312 day). Unfortunately, 52Cr targets are not cost-effective without recycling processes in place, therefore, this work aims to explore routes to prepare Cr targets that could be recycled. Natural Cr foils, metal powder pellets, enriched chromium-52 oxide and Cr(III) electroplated targets were investigated in this work. Each of these cyclotron targets were irradiated, and the produced 52Mn was purified, when possible, using a semi-automated system. An improved purification by solid-phase anion exchange from ethanol-HCl mixtures resulted in recoveries of 94.5 ± 2.2% of 52Mn. The most promising target configuration to produce a recyclable target was electroplated Cr(III). This work presents several pathways to optimize enriched Cr targets for the production of high purity 52Mn.

Abstract Accurate assessment of tumor margins with specific, non-invasive imaging would result in the preservation of healthy tissue and improve long-term local tumor control, thereby reducing the risk of recurrence. Overexpression of epidermal growth factor receptor (EGFR) has been used in other cancers as an imaging biomarker to identify cancerous tissue. We hypothesize that expression of EGFR in ameloblastomas may be used to specifically visualize tumors. The aims of this study are to measure the specificity of radiolabeled 89Zr-panitumumab (an EGFR antibody) in vivo using patient-derived xenograft (PDX) models of ameloblastoma and positron emission tomography/computed tomography (PET/CT) scans. In PDX of ameloblastomas from four patients (AB-36, AB-37, AB-39 AB-53), the biodistribution of 89Zr-panitumumab was measured 120 h post-injection and was reported as the injected dose per gram of tissue (%ID/g; AB-36, 40%; AB-37, 62%; AB-39 18%; AB-53, 65%). The radiolabeled %ID/g was significantly greater in tumors of 89Zr-panitumumab-treated mice that did not receive unlabeled panitumumab as a blocking control for AB-36, AB-37, and AB-53. Radiolabeled anti-EGFR demonstrates specificity for ameloblastoma PDX tumor xenografts, we believe 89Zr-panitumumab is an attractive target for pre-surgical imaging of ameloblastomas. With this technology, we could more accurately assess tumor margins for the surgical removal of ameloblastomas.

Emerging data indicate an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single-cell RNA sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with Streptococcus pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory posttranslational modification of peroxisome proliferator-activated receptor γ (PPARγ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARγ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, individuals residing in areas of high air cadmium levels had increased cadmium concentration in their bronchoalveolar lavage (BAL) fluid, increased barrier dysfunction, and showed PPARγ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARγ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.

Abstract Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p

Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work focuses on a the neurotensin peptide analogue NT-20.3 conjugated to the chelator NOTA for radiolabeling for use in noninvasive positron emission tomography (PET). NOTA-NT-20.3 was radiolabeled with gallium-68, copper-64, and cobalt-55 to determine the effect that modification of the radiometal has on imaging and potential therapeutic properties of NOTA-NT-20.3. Methods: In vitro assays investigating cell uptake and subcellular localization of the radiolabeled peptides were performed using human colorectal adenocarcinoma HT29 cells. In vivo PET/CT imaging was used to determine the distribution and clearance of the peptide in mice bearing NTSR1 expressing HT29 tumors. Results: Cell uptake studies showed that the highest uptake was obtained with [55Co] Co-NOTA-NT-20.3 (18.70 ± 1.30%ID/mg), followed by [64Cu] Cu-NOTA-NT-20.3 (15.46 ± 0.91%ID/mg), and lastly [68Ga] Ga-NOTA-NT-20.3 (10.94 ± 0.46%ID/mg) (p < 0.001). Subcellular distribution was similar across the three constructs, with the membranous fraction containing the highest amount of radioactivity. In vivo PET/CT imaging of the three constructs revealed similar distribution and tumor uptake at the 1 h imaging timepoint. Tumor uptake was receptor-specific and blockable by co-injection of non-radiolabeled NOTA-NT-20.3. SUV ratios of tumor to heart at the 24 h imaging timepoint show that [55Co] Co-NOTA-NT-20.3 (20.28 ± 3.04) outperformed [64Cu] Cu-NOTA-NT-20.3 (6.52 ± 1.97). In conclusion, our studies show that enhanced cell uptake and increasing tumor to blood ratios over time displayed the superiority of [55Co] Co-NOTA-NT-20.3 over [68Ga] Ga-NOTA-NT-20.3 and [64Cu] Cu-NOTA-NT-20.3 for the targeting of NTSR1.

One in eight women will be diagnosed with breast cancer in their lifetime and approximately 25% of those cases will be HER2-positive. Current methods for diagnosing HER2-positive breast cancer involve using IHC and FISH from suspected cancer biopsies to quantify HER2 expression. HER2 PET imaging could potentially increase accuracy and improve the diagnosis of lesions that are not available for biopsies. Using two previously discovered HER2-targeting peptides, we modified each peptide with the chelator DOTA and a PEG2 linker resulting in DOTA-PEG2-GSGKCCYSL (P5) and DOTA-PEG2-DTFPYLGWWNPNEYRY (P6). Each peptide was labeled with 68Ga and was evaluated for HER2 binding using in vitro cell studies and in vivo tumor xenograft models. Both [68Ga]P5 and [68Ga]P6 showed significant binding to HER2-positive BT474 cells versus HER2-negative MDA-MB-231 cells ([68Ga]P5; 0.68 ± 0.20 versus 0.47 ± 0.05 p < 0.05 and [68Ga]P6; 0.55 ± 0.21 versus 0.34 ± 0.12 p < 0.01). [68Ga]P5 showed a higher percent injected dose per gram (%ID/g) binding to HER2-positive tumors two hours post-injection compared to HER2-negative tumors (0.24 ± 0.04 versus 0.12 ± 0.06; p < 0.05), while the [68Ga]P6 peptide showed significant binding (0.98 ± 0.22 versus 0.51 ± 0.08; p < 0.05) one hour post-injection. These results lay the groundwork for the use of peptides to image HER2-positive breast cancer.

Abstract Background In molecular imaging and nuclear medicine, theranostic agents that integrate radionuclide pairs are successfully being used for individualized care, which has led to rapidly growing interest in their continued development. These compounds, which are radiolabeled with one radionuclide for imaging and a chemically identical or similar radionuclide for therapy, may improve patient-specific treatment and outcomes by matching the properties of different radionuclides with a targeting vector for a particular tumor type. One proposed theranostic radionuclide is scandium-47 (47Sc, T 1/2 = 3.35 days), which can be used for targeted radiotherapy and may be paired with the positron emitting radionuclides, 43Sc (T 1/2 = 3.89 h) and 44Sc (T 1/2 = 3.97 h) for imaging. The aim of this study was to investigate the photonuclear production of 47Sc via the 48Ti(γ,p)47Sc reaction using an electron linear accelerator (eLINAC), separation and purification of 47Sc, the radiolabeling of somatostatin receptor-targeting peptide DOTATOC with 47Sc, and in vitro receptor-mediated binding of [47Sc]Sc-DOTATOC in AR42J somatostatin receptor subtype two (SSTR2) expressing rat pancreatic tumor cells. Results The rate of 47Sc production in a stack of natural titanium foils (n = 39) was 8 × 107 Bq/mA·h (n = 3). Irradiated target foils were dissolved in 2.0 M H2SO4 under reflux. After dissolution, trivalent 47Sc ions were separated from natural Ti using AG MP-50 cation exchange resin. The recovered 47Sc was then purified using CHELEX 100 ion exchange resin. The average decay-corrected two-step 47Sc recovery (n = 9) was (77 ± 7)%. A radiolabeling yield of > 99.9% of [47Sc]Sc-DOTATOC (0.384 mg in 0.3 mL) was achieved using 1.7 MBq of 47Sc. Blocking studies using Octreotide illustrated receptor-mediated uptake of [47Sc]Sc-DOTATOC in AR42J cells. Conclusions 47Sc can be produced via the 48Ti(γ,p)47Sc reaction and separated from natural Ti targets with a yield and radiochemical purity suitable for radiolabeling of peptides for in vitro studies. The data in this work supports the potential use of eLINACs for studies of photonuclear production of medical radionuclides and the future development of high-intensity eLINAC facilities capable of producing relevant quantities of carrier-free radionuclides currently inaccessible via routine production pathways or limited due to costly enriched targets.

There is an emerging need for accurate and rapid identification of bacteria in the human body to achieve diverse biomedical objectives. Copper homeostasis is vital for the survival of bacterial species owing to the roles of the metal as a nutrient, respiratory enzyme cofactor, and a toxin. Here, we report the development of a copper-64–labeled bacterial metal chelator, yersiniabactin, to exploit a highly conserved metal acquisition pathway for noninvasive and selective imaging of bacteria. Compared with traditional techniques used to manufacture probes, our strategy simplifies the process considerably by combining the function of metal attachment and cell recognition to the same molecule. We demonstrate, for the first time to our knowledge, how a copper-64 PET probe can be used to identify specific bacterial populations, monitor antibiotic treatment outcomes, and track bacteria in diverse niches in vivo.

ABSTRACT Enterobacteria, including Escherichia coli, bloom to high levels in the gut during inflammation and strongly contribute to the pathology of inflammatory bowel diseases. To survive in the inflamed gut, E. coli must tolerate high levels of antimicrobial compounds produced by the immune system, including toxic metals like copper and reactive chlorine oxidants such as hypochlorous acid (HOCl). Here, we show that extracellular copper is a potent detoxifier of HOCl and that the widely conserved bacterial HOCl resistance enzyme RclA, which catalyzes the reduction of copper(II) to copper(I), specifically protects E. coli against damage caused by the combination of HOCl and intracellular copper. E. coli lacking RclA was highly sensitive to HOCl when grown in the presence of copper and was defective in colonizing an animal host. Our results indicate that there is unexpected complexity in the interactions between antimicrobial toxins produced by innate immune cells and that bacterial copper status is a key determinant of HOCl resistance and suggest an important and previously unsuspected role for copper redox reactions during inflammation. IMPORTANCE During infection and inflammation, the innate immune system uses antimicrobial compounds to control bacterial populations. These include toxic metals, like copper, and reactive oxidants, including hypochlorous acid (HOCl). We have now found that RclA, a copper(II) reductase strongly induced by HOCl in proinflammatory Escherichia coli and found in many bacteria inhabiting epithelial surfaces, is required for bacteria to resist killing by the combination of intracellular copper and HOCl and plays an important role in colonization of an animal host. This finding indicates that copper redox chemistry plays a critical and previously underappreciated role in bacterial interactions with the innate immune system.

Breast cancer continues to be the most lethal cancer type in women and one of the most diagnosed. Understanding Breast cancer receptor status is one of the most vital processes for determining treatment options. One type of breast cancer, human epidermal growth factor receptor 2 (HER2) positive, has approved receptor-based therapies including trastuzumab and pertuzumab that can significantly increase the likelihood of survival. Current methods to determine HER2 status include biopsies with immunohistochemical staining and/or fluorescence in situ hybridization. However, positron emission tomography (PET) imaging techniques using 89 Zr-trastuzumab or 89 Zr-pertuzumab are currently in clinical trials for a non-invasive, full body diagnostic approach. Although the antibodies have strong specificity to the HER2 positive lesions, challenges involving long post-injection time for imaging due to the blood circulation of the antibodies and matching of long-live isotopes leading to increased dose to the patient leave opportunities for alternative PET imaging probes. Peptides have been shown to allow for shorter injection-to-imaging time and can be used with shorter lived isotopes. HER2 specific peptides under development will help improve the diagnosis and potentially therapy options for HER2 positive breast cancer. Peptides showing specificity for HER2 could start widespread development of molecular imaging techniques for HER2 positive cancers.

The emerging success of [68Ga/177Lu]Ga/Lu-DOTATATE as a theranostic pair has spurred interest in other isotopes as potential theranostic combinations. Here, we review cobalt-55 and cobalt-58m as a potential theranostic pair. Radionuclidically pure cobalt-55 and cobalt-58m have been produced on small cyclotrons with high molar activity. In vitro, DOTATOC labeled with cobalt has shown greater affinity for SSTR2 than DOTATOC labeled with gallium and yttrium. Similarly, [58mCo]Co-DOTATATE has shown improved cell-killing capabilities as compared to DOTATATE labeled with either indium-111 or lutetium-177. Finally, PET imaging with an isotope such as cobalt-55 allows for image acquisition at much later timepoints than gallium, allowing for an increased degree of biological clearance of non-bound radiotracer. We discuss the accelerator targetry and radiochemistry used to produce cobalt-55,58m, emphasizing the implications of these techniques to downstream radiotracers being developed for imaging and therapy.

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [89Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [18F]-fluorodeoxyglucose ([18F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [89Zr]-pertuzumab mean standard uptake values (SUVmean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [18F]-FDG SUVmean changes were negatively correlated with [89Zr]-pertuzumab SUVmean (r = −0.5887, p = 0.0030). The baseline [18F]-FDG SUVmean was negatively correlated with initial [89Zr]-pertuzumab SUVmean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies.

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

89Zr has emerged as a useful radioisotope for targeted molecular imaging via positron emission tomography (PET) in both animal models and humans. This isotope is particularly attractive for cancer research because its half-life (t1/2 = 3.27 days) is well-suited for in vivo targeting of macromolecules and nanoparticles to cell surface antigens expressed by cancer cells. Furthermore, 89Zr emits a low-energy positron (Eβ+,mean = 0.40 MeV), which is favorable for high spatial resolution in PET, with an adequate branching ratio for positron emission (BR = 23%). The demand for 89Zr for research purposes is increasing; however, 89Zr also emits significant gamma radiation (Γ15 keV = 6.6 R×cm2/mCi×h), which makes producing large amounts of this isotope by hand unrealistic from a radiation safety standpoint. Fortunately, a straightforward method exists for production of 89Zr by bombarding a natural Y target in a biomedical cyclotron and then separation of 89Zr from the target material by column chromatography. The chemical separation in this method lends itself to remote processing using an automated module placed inside a hot cell. In this work, we have designed, built and commissioned a module that has performed the chemical separation of 89Zr safely and routinely, at activities in excess of 50 mCi, with radionuclidic purity > 99.9% and satisfactory effective specific activity (ESA).

This work describes the production of high–specific activity 55 Co and the evaluation of the stability of 55 Co-metal-chelate-peptide complexes in vivo. 55 Co was produced via the 58 Ni(p,α) 55 Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/μmol. 55 Co-DO3A and 55 Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/μg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55 CoCl 2 . Both 55 Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by sixfold at 24 hours with ˜ 1% ID/g and at 48 hours with ˜ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ˜ 0.7% ID/g and sevenfold at 48 hours with ˜ 0.35% ID/g. These results support the use of 55 Co as a promising new radiotracer for PET imaging of cancer and other diseases.

The goal of this work was to study the efficacy of the positron emission tomography (PET) tracers 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and 64 Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([ 64 Cu]ATSM) and in monitoring placental and fetal functional response to acute hyperoxia in late-term pregnant mice subjected to experimentally induced chronic hypoxia. E15 mice were maintained at 12% inspired oxygen for 72 hours and then imaged during oxygen inhalation with either [ 18 F]FDG to monitor nutrient transport or 64 Cu-ATSM to establish the presence of hypoxia. Computed tomography (CT) with contrast allowed clear visualization of both placentas and fetuses. The average ratio of fetal to placental [ 18 F]FDG uptake was 0.45 ± 0.1 for the hypoxic animals and 0.55 ± 0.1 for the normoxic animals, demonstrating a significant decrease ( p = .0002) in placental function in dams exposed to chronic hypoxic conditions. Hypoxic placentas and fetuses retained more 64 Cu-ATSM compared to normoxic placentas and fetuses. Herein we report first-in-mouse PET imaging of fetuses employing both tracers [ 18 F]FDG (metabolism) and 64 Cu-ATSM (hypoxia). [ 18 F]FDG PET/CT imaging allowed clear visualization of placental-fetal structures and supported quantification of tracer uptake, making this a sensitive tool for monitoring placental function in preclinical rodent models. These measurements illustrate the potentially irreversible damage generated by chronic exposure to hypoxia, which cannot be corrected by acute exposure to hyperoxia.

CD47 functions as a marker of “self” by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET) in both human xenograft and murine allograft tumor models. Anti-CD47 antibodies were conjugated with p -isothiocyanatobenzyldesferrioxamine (Df-Bz-NCS) and labeled with 89 Zr. We employed xenograft and allograft small-animal models of cancer in biodistribution and PET imaging studies to investigate the specificity and PET imaging robustness of CD47. Ab-Df-Bz-NCS conjugates were labeled with 89 Zr with specific activity of 0.9 to 1.6 μCi/μg. Biodistribution studies in the xenograft and allograft model showed similar specific tumor uptake of the antihuman and antimouse CD47 antibodies. However, the tracer retention in the liver, spleen, and kidneys was significantly higher in the allograft-bearing animals, suggesting uptake mediated by the CD47 normally expressed throughout the reticular endothelial system. CD47, a marker of “self,” was evaluated as a diagnostic PET biomarker in xenograft and allograft cancer animal models. CD47 imaging is feasible, warranting further studies and immunoPET tracer development.