Serial Positron Emission Tomography Research Articles

A preclinical PET dual-tracer imaging protocol for ER and HER2 phenotyping in breast cancer xenografts

BackgroundNuclear medicine is on the constant search of precision radiopharmaceutical approaches to improve patient management. Although discordant expression of the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) in breast cancer is a known dilemma for appropriate patient management, traditional tumor sampling is often difficult or impractical. While 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG)-positron emission tomography (PET) is an option to detect subclinical metastases, it does not provide phenotype information. Radiolabeled antibodies are able to specifically target expressed cell surface receptors. However, their long circulating half-lives (days) require labeling with long-lived isotopes, such as 89Zr, in order to allow sufficient time for tracer clearance from the blood compartment and to accumulate adequately in target tumors and, thus, generate high-quality PET images. The aim of this study was to develop a dual-tracer PET imaging approach consisting of a fast-clearing small molecule and a slow-clearing antibody. This approach was evaluated in a model consisting of mice harboring separate breast cancer xenografts with either an ER+/HER2− or ER−/HER2+ phenotype, comparable to human metastatic disease with intertumor heterogeneity. Lastly, the aim of our study was to determine the feasibility of specifically identifying these two important phenotypes in an acceptable time window.MethodsFemale nude mice were subcutaneously implanted on opposite shoulders with the ER+/HER2− and ER−/HER2+ MCF-7 and JIMT-1 tumor cell lines, respectively. A second model was developed consisting of mice implanted orthotopically with either MCF-7 or JIMT-1 cells. Pharmacokinetic analysis, serial PET imaging, and biodistribution were first performed for [89Zr]Zr-DFO-trastuzumab (89Zr-T) up to 8 days post-injection (p.i.) in JIMT-1 bearing mice. Region-of-interest (ROI) and biodistribution-derived uptake (% injected-activity/gram of tissue [%IA/g]) values and tumor-to-background ratios were obtained. Results were compared in order to validate ROI and identify early time points that provided high contrast tumor images. For the dual-tracer approach, cohorts of tumor-bearing mice were then subjected to sequential tracer PET imaging. On day 1, mice were administered 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) which targets ER and imaged 45 min p.i. This was immediately followed by the injection of 89Zr-T. Mice were then imaged on day 3 or day 7. ROI analysis was performed, and uptake was calculated in tumors and selected healthy organs for all radiotracers. Quality of tumor targeting for all tracers was evaluated by tumor contrast visualization, tumor and normal tissue uptake, and tumor-to-background ratios.Results89Zr-T provided sufficiently high tumor and low background uptake values that furnished high contrast tumor images by 48 h p.i. For the dual-tracer approach, 4FMFES provided tumor uptake values that were significantly increased in MCF-7 tumors. When 89Zr-T-PET was combined with 18F-4FMFES-PET, the entire dual-tracer sequential-imaging procedure provided specific high-quality contrast images of ER+/HER2− MCF-7 and ER−/HER2+ JIMT-1 tumors for 4FMFES and 89Zr-T, respectively, as short as 72 h from start to finish.ConclusionsThis protocol can provide high contrast images of tumors expressing ER or HER2 within 3 days from injection of 4FMFES to final scan of 89Zr-T and, hence, provides a basis for future dual-tracer combinations that include antibodies.

In Vivo Tracking of Adoptively Transferred Natural Killer Cells in Rhesus Macaques Using 89Zirconium-Oxine Cell Labeling and PET Imaging.

Trials of adoptive natural killer (NK)-cell immunotherapy for hematologic malignancies have thus far shown only marginal effects, despite the potent in vitro antitumor activity of these cells. Homing of infused cells to tumor microenvironments is critical for efficacy, but has not been well characterized. We established a novel method to track and quantify the distribution of adoptively transferred NK cells using rhesus macaques (RM) as a clinically relevant preclinical model. RM NK cells were expanded ex vivo for 14-21 days, labeled with 89Zr-oxine complex, and assessed for phenotype, function, and survival. Trafficking of 89Zr-labeled ex vivo-expanded NK cells infused into RMs was monitored and quantitated by serial positron emission tomography (PET)/CT (n = 3, 2.05 ± 0.72 MBq, 23.5 ± 2.0 × 106 NK cells/kg) and compared with that of 89Zr-labeled nonexpanded NK cells, apoptotic NK cells, and hematopoietic stem and progenitor cells (HSPC). NK cells retained sufficient levels of 89Zr for accurate in vivo tracking for 7 days. 89Zr labeling did not alter cellular phenotype, viability, or function. PET/CT showed NK cells initially localized in the lungs, followed by their migration to the liver, spleen, and, at low levels, bone marrow. One day following transfer, only 3.4% of infused NK cells localized to the BM versus 22.1% of HSPCs. No clinical side effects were observed, and dosimetry analysis indicated low organ radioexposures of 6.24 mSv/MBq (spleen) or lower. These data support translation of this technique to humans to track the distribution of adoptively infused cells and to develop novel techniques to improve immune cell homing to tumor microenvironments.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: a longitudinal PET study

BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Feasibility of real-time in vivo 89Zr-DFO-labeled CAR T-cell trafficking using PET imaging.

IntroductionChimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET).ResultsThe 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%–79%, and cell radiolabeling activity was 98.1–103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry.ConclusionReal-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.

Assessment of Inflammation in Pulmonary Artery Hypertension by 68Ga-Mannosylated Human Serum Albumin.

Rationale: Diagnosis and monitoring of patients with pulmonary artery hypertension (PAH) is currently difficult.Objectives: We aimed to develop a noninvasive imaging modality for PAH that tracks the infiltration of macrophages into the pulmonary vasculature, using a positron emission tomography (PET) agent, 68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA), that targets the mannose receptor (MR).Methods: We induced PAH in rats by monocrotaline injection. Tissue analysis, echocardiography, and 68Ga-NOTA-MSA PET were performed weekly in rats after monocrotaline injection and in those treated with either sildenafil or macitentan. The translational potential of 68Ga-NOTA-MSA PET was explored in patients with PAH.Measurements and Main Results: Gene sets related to macrophages were significantly enriched on whole transcriptome sequencing of the lung tissue in PAH rats. Serial PET images of PAH rats demonstrated increasing uptake of 68Ga-NOTA-MSA in the lung by time that corresponded with the MR-positive macrophage recruitment observed in immunohistochemistry. In sildenafil- or macitentan-treated PAH rats, the infiltration of MR-positive macrophages by histology and the uptake of 68Ga-NOTA-MSA on PET was significantly lower than that of the PAH-only group. The pulmonary uptake of 68Ga-NOTA-MSA was significantly higher in patients with PAH than normal subjects (P = 0.009) or than those with pulmonary hypertension by left heart disease (P = 0.019) (n = 5 per group).Conclusions:68Ga-NOTA-MSA PET can help diagnose PAH and monitor the inflammatory status by imaging the degree of macrophage infiltration into the lung. These observations suggest that 68Ga-NOTA-MSA PET has the potential to be used as a novel noninvasive diagnostic and monitoring tool of PAH.

SERIAL RUBIDIUM-82 CARDIAC PET IMAGING EARLY POST HEART TRANSPLANT PREDICTS ADVERSE CARDIOVASCULAR OUTCOMES

Myocardial blood flow (MBF) quantification by Rubidium-82 (Rb82) positron emission tomography (PET) has shown utility for cardiac allograft vasculopathy surveillance and cardiovascular risk stratification post heart transplantation (HT). The objective of this study was to determine the prognostic value of serial Rubidium-82 PET examinations performed early after HT.

Positron emission tomography reporter gene strategy for use in the central nervous system

There is a growing need for monitoring or imaging gene therapy in the central nervous system (CNS). This can be achieved with a positron emission tomography (PET) reporter gene strategy. Here we report the development of a PET reporter gene system using the PKM2 gene with its associated radiotracer [18F]DASA-23. The PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. Serial PET imaging was carried out over 8 wk to assess PKM2 expression. After 8 wk, the brains were excised for further mRNA and protein analysis. PET imaging at 8 wk post-AAV delivery showed an increase in [18F]DASA-23 brain uptake in the transduced site of mice injected with the AAV mice over all controls. We believe PKM2 shows great promise as a PET reporter gene and to date is the only example that can be used in all areas of the CNS without breaking the blood-brain barrier, to monitor gene and cell therapy.

Impact of different image reconstructions on PET quantification in non-small cell lung cancer: a comparison of adenocarcinoma and squamous cell carcinoma

Positron emission tomography (PET) using 18F-fludeoxyglucose (18F-FDG) is an established imaging modality for tumor staging in patients with non-small cell lung cancer (NSCLC). There is a growing interest in using 18F-FDG PET for therapy response assessment in NSCLC which relies on quantitative PET parameters such as standardized uptake values (SUV). Different reconstruction algorithms in PET may affect SUV. We sought to determine the variation of SUV in patients with NSCLC when using ordered subset expectation maximization (OSEM) and block sequential regularized expectation maximization (BSREM) in latest-generation digital PET/CT, including a subanalysis for adenocarcinoma and squamous cell carcinoma. A total of 58 patients (34 = adenocarcinoma, 24 = squamous cell carcinoma) who underwent a clinically indicated 18F-FDG PET/CT for staging were reviewed. PET images were reconstructed with OSEM and BSREM reconstruction with noise penalty strength β-levels of 350, 450, 600, 800 and 1200. Lung tumors maximum standardized uptake value (SUVmax) were compared. Lung tumors SUVmax were significantly lower in adenocarcinomas compared to squamous cell carcinomas in all reconstructions evaluated (all p < 0.01). Comparing BSREM to OSEM, absolute SUVmax differences were highest in lower β-levels of BSREM with + 2.9 ± 1.6 in adenocarcinoma and + 4.0 ± 2.9 in squamous cell carcinoma (difference between histology; p-values > 0.05). There was a statistically significant difference of the relative increase of SUVmax in adenocarcinoma (mean + 34.8%) and squamous cell carcinoma (mean 23.4%), when using BSREM350 instead of OSEMTOF (p < 0.05). In NSCLC the relative change of SUV when using BSREM instead of OSEM is significantly higher in adenocarcinoma as compared to squamous cell carcinoma. The impact of BSREM on SUV may vary in different histological subtypes of NSCLC. This highlights the importance for careful standardization of β-value used for serial 18F-FDG PET scans when following-up NSCLC patients.

Role of Serial Positron Emission Tomography (PET) Scans in Indolent Lymphomas' Management - Interim Results from an Ongoing Prospective Study at King Fahd Medical City, Riyadh, Saudi Arabia

Background:Indolent lymphomas (ind-LYM) are a subset of B-cell lymphomas, characterized by slow growth, protracted course without treatment and a tendency to reoccur after therapy. The management of ind-LYM is varied and evolving. To-date reliable tools for imaging based prognostication and treatment strategies are limited. We explored the utility of serial FDG PET scans (baseline (BL), interim/6 months (INT) end of therapy/1 year (EOT)), in managing ind-LYM).Methods:From an ongoing prospective study, examining the role of PET scan in ind-LYM at our institution, we performed an interim analysis of all patients hitherto enrolled in our study. Patients diagnosed as ind-LYM and having undergone serial PET scans from 2015 to date (N=40, males= 27, females =13) had median age of 59.68 ± 14.5 (28-82 at diagnosis. All PET scans were obtained per accepted protocols. SUVmax and Deauville scores (DS) were obtained from five target lesions. The average of composite SUV (cSUV) and composite Deauville scores (cDS) were computed for each patient. Statistical analyses (using t-test, mean delta change) were performed with the cSUV and cDS.Results:The types of ind-LYM were CLL/SLL (17), Follicular (15), mantle cell (3), marginal zone lymphoma (3), and 1 each of MALT and lymphoplasmacytic lymphoma. The data were analyzed for two arms of the study treatment chemotherapy arm (CHEMO-22/40) and Rituximab + observation arm (OBSR-18/40). At BL, patients on CHEMO had significantly higher cSUV and cDS compared to those who were on OBSR (SUV: 6.99 vs. 4.32 p-value 0.0124; cDS: 4.37 vs 3.71 p-value 0.0075 respectively). Although there was a delta change in the cSUV and cDS in both arms after INT and EOT, both treatment lines showed no significant difference in the SUV mean and DS (p-value: 0.754 and 0.5721, receptively). A 2-tailed T-test was used for delta change of cSUV. BL to INT cSUV was statistically significant (p-valve 0.05) and difference in cSUV was not significant for BL to EOT (p-valve 0.98). Difference in cDS was not significant between BL, INT and EOT.Conclusion:The higher cSUV/cDS at BL for the treatment arm may be due to disease profile at the time of presentation and/or selection bias. At EOT no difference in both estimates were noted. Both arms showed similar trends in delta change from BL-INT-EOT. Our findings suggest that SUV and DS at BL maybe an independent criterion for treatment selection in ind-LYM. DisclosuresNo relevant conflicts of interest to declare.

64cu-DOTA-Anti-CD33 PET-CT Imaging for Acute Myeloid Leukemia and Image-Guided Treatment

Introduction:Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results a poor survival outcome. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). Although non-invasive positron emission tomography (PET) imaging has been developed for almost all solid tumors and some hematological malignancies, there is currently no non-invasive imaging specific to AML available, representing an unmet clinical need. About 85% of AML cells express CD33, and expression levels of CD33 has been correlated with poor survival outcomes (Pollard et al., Blood (2012)), making it an ideal candidate for immuno-PET. Therefore, our primary goal is to develop anti-CD33 immuno-PET for detecting CD33+ AML. The secondary goal is to assess the feasibility of CD33 PET image-guided external beam targeted radiation delivery in combination with chemotherapy (AraC).Methods:Murine anti-human CD33 monoclonal antibody clone p67.6 was conjugated to DOTA and radiolabeled with Cu-64 for imaging studies. In vivo PET-CT imaging and bio distribution of 64Cu-DOTA-anti-CD33 in vivo was carried out in NSG mice bearing CD33+ (MV4-11, HL60) AML cells. CD33-negative MM1s cells (multiple myeloma) were used as negative control. The AML and MM bearing mice were injected with 64Cu-DOTA-anti-CD33 (100 µCi/10 µg) and serial PET imaged at 24-48 h.We developed a functional total marrow irradiation (fTMI) treatment, where mice received total marrow irradiation (TMI) (2 Gy) and boost radiation (2 Gy) to regions with increased CD33 activity, followed by 2 days of AraC (40 mg/kg) and 24h later a bone marrow transplant. Furthermore, a humanized anti-human CD33 monoclonal antibody was generated and tested for immunogenicity against CD33 in AML cell lines and patient samples for future clinical studies.Results:PET-CT imaging and biodistribution studies of 64Cu-DOTA-anti-CD33 clearly indicates a CD33+ PET signal in the femur, tibia, humerus joints, L spine and spleen in AML-bearing mice, but not in multiple myeloma-bearing mice or in cold anti-CD33-DOTA treated leukemic mice (Figure 1A and B). Our new imaging method was able to detect CD33+ AML with a favorable sensitivity (71.4%) and specificity (100%). Based on detailed whole-body 3D imaging and validated with biodistribution studies, we discovered preferential regions in the skeletal system with differential CD33 activity, indicating the spatial heterogeneity of AML. CD33+ PET intensity was observed in the following descending order: femur≥lspine>humerus>tibia (Figure 1C).Next, using the PET-CT images, we targeted these CD33-active regions using the fTMI treatment plan. We have developed a unique irradiation system which allows targeting only skeletal tissues while sparing major organs like gut, lung and liver, unlike conventional total body irradiation (TBI). This approach will also provide an opportunity to escalate doses to specific regions in the body without damaging other unintended targets. The fTMI (2 Gy TMI and 2 Gy boost) treatment plan increased the medial survival of the mice to 43 days versus that of untreated control mice (26 days) or AraC treated mice (33 days) Figure(1D).Since the preclinical study was carried out using murine anti-CD33 antibody clone p67.6, we further tested the newly generated humanized anti-human-CD33 monoclonal antibody. This humanized antibody detects CD33 in both AML cell lines and human patient sample (Fig 1E).Conclusion:This study is the first to use an anti-CD33 monoclonal antibody for non-invasive immuno-PET-based imaging for AML detection, showing high sensitivity and specificity. This whole body imaging may be useful for AML diagnosis not only in the entire skeletal system, but also in the extramedullary organs, and for longitudinal monitoring of treatment response. Unlike conventional TBI, Image-guided fTMI along with conventional chemotherapy may result in an improved prognosis, as unintended major organs are spared from radiation. [Display omitted] DisclosuresVallera:GT Biopharma: Consultancy, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.

Diet-Modulated Lipoprotein Metabolism and Vascular Inflammation Evaluated by 18F-fluorodeoxyglucose Positron Emission Tomography.

Vascular inflammation plays a central role in atherosclerosis, from initiation and progression to acute thrombotic complications. Modified low-density lipoproteins (LDLs) and apoB-containing particles stimulate plaque inflammation by interacting with macrophages. Loss of function of high-density lipoprotein (HDL) for preventing LDL particles from oxidative modification in dyslipidemic states may amplify modified LDL actions, accelerating plaque inflammation. Diets are one of the most important factors that can affect these processes of lipoprotein oxidation and vascular inflammation. Recently, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as a reliable noninvasive imaging modality for identifying and quantifying vascular inflammation within atherosclerotic lesions based on the high glycolytic activity of macrophages infiltrating active atherosclerotic plaques. Vascular inflammation evaluated by FDG PET has been positively related to metabolic syndrome components and traditional risk factors of cardiovascular disease, including high-sensitivity C-reactive protein, body mass index, and insulin resistance. A positive association of vascular inflammation with endothelial dysfunction, resistin levels, pericardial adipose tissue, and visceral fat area has also been reported. In contrast, HDL cholesterol and adiponectin have been inversely related to vascular inflammation detected by FDG PET. Because of its reproducibility, serial FDG PET shows potential for tracking the effects of dietary interventions and other systemic and local antiatherosclerotic therapies for plaque inflammation.

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.

Spatial and temporal evolution of lung granulomas in a cynomolgus macaque model of Mycobacterium tuberculosis infection

BackgroundLittle is known about granuloma progression of Mycobacterium tuberculosis infection in humans. Using serial positron emission tomography and computed tomography (PET/CT) of an animal model that recapitulates human infection with M. tuberculosis, we are able to track lung granulomas. ObjectiveWe characterized the spatial and temporal pattern of granuloma formation during primary infection and reactivation. MethodsSerial PET/CT was performed on cynomolgus macaques (n = 28) during primary and reactivation M. tuberculosis infection. Distances between granulomas during the first six weeks post infection (“primary” granulomas) were compared to new granulomas that developed afterwards (“secondary” granulomas) using nearest neighbor analysis during primary infection, reactivation and between different routes of infection. ResultsSecondary granulomas developed within 2 cm of a primary granuloma within the same lung lobe with 80% probability during the course of primary infection, and this same pattern was observed during reactivation of latent infection after immune suppression. Using a logistic growth function, we were able to predict the maximum number of granulomas that would develop over the course of infection with good correlation (R2 = 0.96). ConclusionThese data provide important insights into the dynamic patterns of bacterial dissemination during the earliest phases of primary infection and reactivation tuberculosis.

Influence of Dexamethasone on O-(2-[18F]-Fluoroethyl)-L-Tyrosine Uptake in the Human Brain and Quantification of Tumor Uptake.

O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence of dexamethasone therapy on [18F]FET uptake in the normal brain and its influence on the maximum and mean tumor-to-brain ratio (TBR). [18F]FET PET scans of 160 brain tumor patients were evaluated (80 dexamethasone treated, 80 untreated; each group with 40 men/40 women). The standardized uptake value of [18F]FET uptake in the normal brain (SUVbrain) in the different groups was compared. Nine patients were examined repeatedly with and without dexamethasone therapy. SUVbrain of [18F]FET uptake was significantly higher in dexamethasone-treated patients than in untreated patients (SUVbrain 1.33 ± 0.1 versus 1.06 ± 0.16 in male and 1.45 ± 0.25 versus 1.31 ± 0.28 in female patients). Similar results were observed in patients with serial PET scans. Furthermore, compared to men, a significantly higher SUVbrain was found in women, both with and without dexamethasone treatment. There were no significant differences between the different groups for TBRmax and TBRmean, which could have been masked by the high standard deviation. In a patient with a stable brain metastasis investigated twice with and without dexamethasone, the TBRmax and the biological tumor volume (BTV) decreased considerably after dexamethasone due to an increased SUVbrain. Dexamethasone treatment appears to increase the [18F]FET uptake in the normal brain. An effect on TBRmax, TBRmean, and BTV cannot be excluded which should be considered especially for treatment monitoring and the estimation of BTV using [18F]FET PET.

86/90Y-Based Theranostics Targeting Angiogenesis in a Murine Breast Cancer Model.

Angiogenesis is widely recognized as one of the hallmarks of cancer. Therefore, imaging and therapeutic agents targeted to angiogenic vessels may be widely applicable in many types of cancer. To this end, the theranostic isotope pair, 86Y and 90Y, were used to create a pair of agents for targeted imaging and therapy of neovasculature in murine breast cancer models using a chimeric anti-CD105 antibody, TRC105. Serial positron emission tomography imaging with 86Y-DTPA-TRC105 demonstrated high uptake in 4T1 tumors, peaking at 9.6 ± 0.3%ID/g, verified through ex vivo studies. Additionally, promising results were obtained in therapeutic studies with 90Y-DTPA-TRC105, wherein significantly ( p < 0.05) decreased tumor volumes were observed for the targeted treatment group over all control groups near the end of the study. Dosimetric extrapolation and tissue histological analysis corroborated trends found in vivo. Overall, this study demonstrated the potential of the pair 86/90Y for theranostics, enabling personalized treatments for cancer.

Intrinsically Zirconium-89-Labeled Manganese Oxide Nanoparticles for In Vivo Dual-Modality Positron Emission Tomography and Magnetic Resonance Imaging.

Manganese-based nanoparticles (NPs) have recently attracted much attention in the field of biomedical imaging due to their impressive enhanced T1 contrast ability. Although the reported manganese-based NPs have exhibited good imaging capabilities as contrast agents, it is still urgent to develop novel multifunctional manganese-based imaging probes for future biomedical imaging, especially PET/MRI probes. Herein, we present chelator-free zirconium-89 (89Zr, t1/2: 78.4 h) labeling of manganese oxide NPs (Mn3O4@PEG) with ∼78% labeling yield and good stability. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies non-invasively assessed the biodistribution patterns of the NPs and the feasibility of in vivo dual-modality imaging and lymph-node mapping. Since Mn3O4 NPs exhibited desirable properties for enhanced T1 imaging and the simplicity of chelator-free radiolabeling, [89Zr]Mn3O4@PEG NPs offer a novel, simple, safe and accurate nanoplatforms for future precise cancer imaging and diagnosis.

The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole

Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography.

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma

BackgroundI-124 codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in patients with hepatocellular carcinoma (HCC). Fourteen patients with HCC underwent baseline imaging with I-124 codrituzumab (~ 185 MBq, 10 mg). Seven of these patients undergoing sorafenib/immunotherapy with 2.5 or 5 mg/kg of cold codrituzumab had repeat imaging, with co-infusion of I-124 codrituzumab, as part of their immunotherapy treatment. Three patients who progressed while on sorafenib/immunotherapy were re-imaged after a 4-week washout period to assess for the presence of antigen. Serial positron emission tomography (PET) imaging and pharmacokinetics were performed following I-124 codrituzumab. An ELISA assay was used to determine “cold” codrituzumab serum pharmacokinetics and compare it to that of I-124 codrituzumab. Correlation of imaging results was performed with IHC. Short-term safety assessment was also evaluated.ResultsThirteen patients had tumor localization on baseline I-124 codrituzumab; heterogeneity in tumor uptake was noted. In three patients undergoing repeat imaging while on immunotherapy/sorafenib, evidence of decreased I-124 codrituzumab uptake was noted. All three patients who underwent imaging after progression while on immunotherapy continued to have I-124 codrituzumab tumor uptake. Pharmacokinetics of I-124 codrituzumab was similar to that of other intact IgG. No significant adverse events were observed related to the I-124 codrituzumab.ConclusionsI-124 codrituzumab detected tumor localization in most patients with HCC. Pharmacokinetics was similar to that of other intact iodinated humanized IgG. No visible cross-reactivity with normal organs was observed.

Myocardial Inflammation Predicts Remodeling and Neuroinflammation After Myocardial Infarction

BackgroundThe local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration. ObjectivesThis study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis. MethodsAfter coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9). ResultsInfarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68+ inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (rpartial = −0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls. ConclusionsThe brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes.