-
Frontiers in Immunology 2023Non-invasive imaging techniques such as positron emission tomography (PET) are extremely important for cancer detection and characterization especially for difficult to...
High folate receptor expression in gliomas can be detected using folate-based positron emission tomography with high tumor-to-brain uptake ratio divulging potential future targeting possibilities.
INTRODUCTION
Non-invasive imaging techniques such as positron emission tomography (PET) are extremely important for cancer detection and characterization especially for difficult to biopsy or extremely delicate organs such as the brain. The folate analogue 1,4,7-triazacylononane-1,4,7-triacetic acid-conjugated folate radiolabeled with aluminum fluoride-18 ([F]FOL) has been previously shown to accumulate preferentially in tumor cells with an overexpression of folate receptors (FRs) and here was investigated for its ability to detect orthotopic gliomas in a rat model. In addition, we studied the expression of FRs in human glioblastoma samples to investigate if an analogous relationship may exist.
METHODS
Nine BDIX rats were injected with BT4C rat glioma cells into the right hemisphere of the brain. Animals were imaged with gadolinium-enhanced magnetic resonance imaging at on days prior to PET/computed tomography (CT) imaging. Animals were divided into two groups, and were PET/CT imaged with either [F]FOL or 2-deoxy-2-18F-fluoro-D-glucose ([F]FDG) on 19 and 32-days post glioma grafting. Two subjects were also PET/CT imaged with [F]FOL on day 16. Biodistribution was studied and brains were cryosectioned for autoradiography, immunofluorescence, and histological studies. Patient-derived paraffin-embedded glioblastomas were sectioned and stained with similar methods.
RESULTS
PET imaging showed an increase of [18F]FOL tumor-to-brain uptake ratio (TBR) over the study duration from day 16/19 (3.3 ± 0.9) increasing to 5.7 ± 1.0 by day 32. [F]FDG PET-imaged rats had a consistent TBR of 1.6 ± 0.1 throughout the study. Ex vivo autoradiography results revealed an exceptionally high TBR of 116.1 ± 26.9 for [F]FOL while the [18F]FDG values were significantly lower giving 2.9 ± 0.6 (P<0.0001). Immunostaining demonstrated an increased presence of FR-α in the BT4C gliomas versus the contralateral brain tissue, while FR-β was present only on glioma periphery. Human sections assayed showed similar FRs expression characteristics.
CONCLUSION
This study shows upregulation of FR-α inside glioma regions in both human and animal tissue, providing a biochemical basis for the observed increased [F]FOL uptake in animal PET images. These results suggest that FRs targeting imaging and therapeutic compounds may possess clinically relevant translational abilities for the detection and treatment of gliomas.
Topics: Rats; Humans; Animals; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Folic Acid; Tissue Distribution; Radiopharmaceuticals; Positron-Emission Tomography; Glioma; Brain; Glioblastoma
PubMed: 37275898
DOI: 10.3389/fimmu.2023.1145473 -
Antimicrobial Agents and Chemotherapy Aug 2022Lefamulin, a semisynthetic pleuromutilin antibiotic approved in the United States, Canada, and Europe for intravenous and oral treatment of community-acquired bacterial...
Lefamulin, a semisynthetic pleuromutilin antibiotic approved in the United States, Canada, and Europe for intravenous and oral treatment of community-acquired bacterial pneumonia, is highly active against bacterial pathogens that cause sexually transmitted infections (STIs), including multidrug-resistant strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium. This nonclinical study used quantitative whole-body autoradiography (QWBA) and qualitative tape-transfer microautoradiography (MARG) to investigate lefamulin distribution into urogenital tract tissues down to a cellular level in male and female rats. A single intravenous dose (30 mg/kg) of [C]-lefamulin was administered to 3 male and 3 female Sprague-Dawley rats. At 0.5, 6, and 24 h post dose, rats were euthanized and [C]-lefamulin distribution was investigated using QWBA and MARG of sagittal planes. [C]-lefamulin was well distributed throughout the carcasses of male and female rats, with the highest concentrations observed in male bulbourethral gland, urethra, prostate in female clitoral gland, uterus (particularly endometrium), and ovary. In these areas, concentrations were similar to or higher than those observed in the lungs. Concentrations peaked at 0.5 h post dose, remaining detectable in the urogenital tract up to 24 h post dose. [C]-lefamulin in rats showed rapid, homogeneous distribution into urogenital tissues down to a cellular level, with high tissue:blood ratios in tissues relevant to STI treatment. These results, and the potent activity of lefamulin against multidrug-resistant bacteria known to cause STIs, will help inform further assessment of lefamulin, including potential clinical evaluation for treatment of STIs.
Topics: Animals; Anti-Bacterial Agents; Chlamydia trachomatis; Community-Acquired Infections; Diterpenes; Female; Male; Pneumonia; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Sexually Transmitted Diseases; Thioglycolates; Tissue Distribution
PubMed: 35862748
DOI: 10.1128/aac.00355-22 -
Cancers Apr 2023The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However,...
UNLABELLED
The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However, its ability to detect low-grade tumor lesions is not optimal.
METHODS
First, we prospectively performed neurotensin receptor-1 (NTS) IHC in a series of patients receiving both [Ga]Ga-PSMA-617 and [Ga]Ga-RM2 before prostatectomy. In this series, PSMA and GRP-R IHC were also available (n = 16). Next, we aimed at confirming the PSMA/GRP-R/NTS expression profile by retrospective autoradiography (n = 46) using a specific radiopharmaceuticals study and also aimed to decipher the expression of less-investigated targets such as NTS, SST and CXCR4.
RESULTS
In the IHC study, all samples with negative PSMA staining (two patients with ISUP 2 and one with ISUP 3) were strongly positive for NTS staining. No samples were negative for all three stains-for PSMA, GRP-R or NTS. In the autoradiography study, binding of [In]In-PSMA-617 was high in all ISUP groups. However, some samples did not bind or bound weakly to [In]In-PSMA-617 (9%). In these cases, binding of [n]In-JMV 6659 and [In]In-JMV 7488 towards NTS and NTS was high.
CONCLUSIONS
Targeting PSMA and NTS/NTS could allow for the detection of all intraprostatic lesions.
PubMed: 37190273
DOI: 10.3390/cancers15082345 -
ACS Infectious Diseases Dec 2019Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on...
Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, -infected mice over 48 h. After the intravenous injection, Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.
Topics: Administration, Intravenous; Animals; Autoradiography; Diarylquinolines; Disease Models, Animal; Female; Humans; Lung; Mice; Positron-Emission Tomography; Tuberculosis; Whole Body Imaging
PubMed: 31345032
DOI: 10.1021/acsinfecdis.9b00207 -
Journal of Neuropathology and... Sep 2019The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today, with an overall rate of 0.39/1000 live births.... (Review)
Review
The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today, with an overall rate of 0.39/1000 live births. It is defined as the sudden and unexpected death of an infant <12 months of age that remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. The serotonin brainstem hypothesis has been a leading hypothesis for SIDS over the last 2 decades. Our laboratory has studied this hypothesis over time with a variety of tissue techniques, including tissue receptor autoradiography, high performance liquid chromatography, Western blot analysis, immunocytochemistry, and proteomics. The purpose of this article is to review the progress in our laboratory toward supporting this hypothesis. We conclude that an important subset of SIDS infants has serotonergic abnormalities resulting from a "core lesion" in the medullary reticular formation comprised of nuclei that contain serotonin neurons. This lesion could lead to a failure of protective brainstem responses to homeostatic challenges during sleep in a critical developmental period which cause sleep-related sudden death.
Topics: Brain Stem; Humans; Infant; Infant, Newborn; Midbrain Reticular Formation; Serotonergic Neurons; Serotonin; Sudden Infant Death
PubMed: 31397480
DOI: 10.1093/jnen/nlz062 -
NeuroImage Dec 2022Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the...
Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT, CB, D, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.
Topics: Humans; Receptors, Neurotransmitter; Brain; Autoradiography; Neurotransmitter Agents; Carrier Proteins; Gene Expression
PubMed: 36209794
DOI: 10.1016/j.neuroimage.2022.119671 -
European Journal of Nuclear Medicine... Jan 2022The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer's disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an...
BACKGROUND
The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer's disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD.
AIM
To synthesize a new Aβ tracer [F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects.
METHODS
[F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [F]DRKXH1 were investigated. Small-animal-PET was used for [F]DRKXH1 and [F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [F]DRKXH1.
RESULTS
The yield of [F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [F]DRKXH1. The concentration of [F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0-60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. The DVR value of [F]-DRKXH1 is higher than that of [F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake.
CONCLUSIONS
[F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Humans; Mice; Mice, Transgenic; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Tissue Distribution
PubMed: 34292345
DOI: 10.1007/s00259-021-05421-0 -
Molecular Pharmaceutics Oct 2022Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is...
Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase IX (CAIX). Therefore, noninvasive imaging of CAIX could be of prognostic value, and it could steer treatment strategies. The aim of this study was to compare variants of CAIX-binding VHH B9, with and without a C-terminal albumin-binding domain with varying affinity (ABD and ABD), for SPECT imaging of CAIX expression. The binding affinity and internalization of the various B9-variants were analyzed using SK-RC-52 cells. Biodistribution studies were performed in mice with subcutaneous SCCNij153 human head and neck cancer xenografts. Tracer uptake was determined by radioactivity counting and visualized by SPECT/CT imaging. Furthermore, autoradiography images of tumor sections were spatially correlated with CAIX immunohistochemistry. B9-variants demonstrated a similar moderate affinity for CAIX . Maximal tumor uptake and acceptable tumor-to-blood ratios were found in the SCCNij153 model at 4 h post injection for [In]In-DTPA-B9 (0.51 ± 0.08%ID/g and 8.1 ± 0.85, respectively), 24 h post injection for [In]In-DTPA-B9-ABD (2.39 ± 0.44%ID/g and 3.66 ± 0.81, respectively) and at 72 h post injection for [In]In-DTPA-B9-ABD (8.7 ± 1.34%ID/g and 2.43 ± 0.15, respectively) An excess of unlabeled monoclonal anti-CAIX antibody efficiently inhibited tumor uptake of [In]In-DTPA-B9, while only a partial reduction of [In]In-DTPA-B9-ABD and [In]In-DTPA-B9-ABD uptake was found. Immunohistochemistry and autoradiography images showed colocalization of all B9-variants with CAIX expression; however, [In]In-DTPA-B9-ABD and [In]In-DTPA-B9-ABD also accumulated in non-CAIX expressing regions. Tumor uptake of [In]In-DTPA-B9-ABD and [In]In-DTPA-B9-ABD, but not of [In]In-DTPA-B9, could be visualized with SPECT/CT imaging. In conclusion, [In]In-DTPA-B9 has a high affinity to CAIX and shows specific targeting to CAIX in head and neck cancer xenografts. The addition of ABD prolonged plasma half-life, increased tumor uptake, and enabled SPECT/CT imaging. This uptake was, however, partly CAIX- independent, precluding the ABD-tracers for use in hypoxia quantification in this tumor type.
Topics: Albumins; Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Carbonic Anhydrase IX; Cell Line, Tumor; Half-Life; Head and Neck Neoplasms; Humans; Hypoxia; Mice; Pentetic Acid; Tissue Distribution; Tomography, Emission-Computed, Single-Photon
PubMed: 35044182
DOI: 10.1021/acs.molpharmaceut.1c00841 -
Molecular Imaging 2020Positron-emitting nuclides have long been used as imaging agents in medical science to spatially trace processes non-invasively, allowing for real-time molecular imaging... (Review)
Review
Positron-emitting nuclides have long been used as imaging agents in medical science to spatially trace processes non-invasively, allowing for real-time molecular imaging using low tracer concentrations. This ability to non-destructively visualize processes in real time also makes positron imaging uniquely suitable for probing various processes in plants and porous environmental media, such as soils and sediments. Here, we provide an overview of historical and current applications of positron imaging in environmental research. We highlight plant physiological research, where positron imaging has been used extensively to image dynamics of macronutrients, signalling molecules, trace elements, and contaminant metals under various conditions and perturbations. We describe how positron imaging is used in porous soils and sediments to visualize transport, flow, and microbial metabolic processes. We also address the interface between positron imaging and other imaging approaches, and present accompanying chemical analysis of labelled compounds for reviewed topics, highlighting the bridge between positron imaging and complementary techniques across scales. Finally, we discuss possible future applications of positron imaging and its potential as a nexus of interdisciplinary biogeochemical research.
Topics: Electrons; Plants; Radioactive Tracers; Soil
PubMed: 33119419
DOI: 10.1177/1536012120966405 -
EJNMMI Research Jul 2022Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by...
BACKGROUND
Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here.
METHODS
In vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [C]MPC-6827. Additionally, α, β, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays.
RESULTS
Cell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower β tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results.
CONCLUSIONS
Collectively, our data indicate that [C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies.
PubMed: 35881263
DOI: 10.1186/s13550-022-00912-z