[<Superscript>18</Superscript>F]FDG PET Neuroimaging Predicts Pentylenetetrazole (PTZ) Kindling Outcome in Rats

Purpose

Epileptogenesis, i.e., development of epilepsy, involves a number of processes that alter the brain function in the way that triggers spontaneous seizures. Kindling is one of the most used animal models of temporal lobe epilepsy (TLE) and epileptogenesis, although chemical kindling suffers from high inter-assay success unpredictability. This study was aimed to analyze the eventual regional brain metabolic changes during epileptogenesis in the pentylenetetrazole (PTZ) kindling model in order to obtain a predictive kindling outcome parameter.

Procedures

In vivo longitudinal positron emission tomography (PET) scans with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) along the PTZ kindling protocol (35 mg/kg intraperitoneally (i.p.), 18 sessions) in adult male rats were performed in order to evaluate the regional brain metabolism.

Results

The half of the PTZ-injected rats reached the kindled state. In addition, a significant decrease of [¹⁸F]FDG uptake at the end of the protocol in most of the brain structures of kindled animals was found, reflecting the characteristic epilepsy-associated hypometabolism. However, PTZ-injected animals but not reaching the kindled state did not show this widespread brain hypometabolism. Retrospective analysis of the data revealed that hippocampal [¹⁸F]FDG uptake normalized to pons turned out to be a predictive index of the kindling outcome. Thus, a 19.06 % reduction (p?=?0.008) of the above parameter was found in positively kindled rats compared to non-kindled ones just after the fifth PTZ session.

Conclusion

Non-invasive PET neuroimaging was a useful tool for discerning epileptogenesis progression in this animal model. Particularly, the [¹⁸F]FDG uptake of the hippocampus proved to be an early predictive parameter to differentiate resistant and non-resistant animals to the PTZ kindling.

     

The Effect of Defective PET Detectors in Clinical Simultaneous [<Superscript>18</Superscript>F]FDG Time-of-Flight PET/MR Imaging

Purpose

The purpose of this study was to evaluate the effect of defective positron emission tomography (PET) detectors on clinical PET image quality in simultaneous PET/magnetic resonance imaging (MRI) for both time-of-flight (TOF) and non-TOF reconstructed images.

Procedures

A total of six patients with various malignant tumors were included and underwent a 2-deoxy-2-[¹⁸F]fluoro-d-glucose PET scan in a fully functional simultaneous TOF PET/MRI. TOF and non-TOF PET images were reconstructed before and after simulating defective detector units. All images were clinically assessed and scored. In addition, a quantitative assessment was performed. Differences were ascertained and compared using the Wilcoxon matched pairs signed-rank test.

Results

Without TOF, the image artifacts introduced by one defective detector unit already started to degrade the overall image quality. It reduced the confidence and could lead to a change in diagnosis. Simulating three or five defective detector units resulted in more artifacts and further reduced overall image quality and confidence. By including TOF information, the effects were mitigated: Images reconstructed with one defective detector unit had similar scores as the ones without defective units. The average absolute percentage error for one, three, and five defective detector units were respectively 8, 20, and 37 % for the non-TOF cases and only 5, 11, and 19 % for the TOF cases.

Conclusion

Our study indicates that PET image artifacts due to (simulated) defective detectors are significantly mitigated with the integration of TOF information in simultaneous PET/MR. One defective detector unit introduces, on average, a 5 % absolute percentage error. However, in TOF imaging, even in cases with one or three defective units for head and neck imaging and one defective unit for chest and abdominal imaging, overall image quality, artifact scoring, and reader confidence are not significantly degraded.

     

Coupled Imaging with [<Superscript>18</Superscript>F]FBB and [<Superscript>18</Superscript>F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain

Purpose

The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2-[¹⁸F]fluoro -D-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2-{2-[2-[¹⁸F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [¹⁸F]FBB) in a group of patients affected by Alzheimer’s disease (AD).

Procedures

We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [¹⁸F]FDG and [¹⁸F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [¹⁸F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [¹⁸F]FDG PET/CT scans.

Results

SPM analysis in AD patients showed a significant negative correlation between [¹⁸F] FBB and [¹⁸F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group.

Conclusions

Combined imaging with [¹⁸F]FBB and [¹⁸FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD.

     

Evaluation of TSPO PET Ligands [<Superscript>18</Superscript>F]VUIIS1009A and [<Superscript>18</Superscript>F]VUIIS1009B: Tracers for Cancer Imaging

Purpose

Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.

Procedures

VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D ¹H-¹⁵N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [¹⁸F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.

Results

Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC₅₀ values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B exhibited greater binding potential (k ₃/k ₄)in tumor tissue compared to [¹⁸F]DPA-714. Interestingly, [¹⁸F]VUIIS1009B exhibited significantly greater tumor uptake (V _T) than [¹⁸F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.

Conclusions

The novel PET ligand [¹⁸F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [¹⁸F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [¹⁸F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

     

An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[<Superscript>18</Superscript>F]Fluorobenzyl-Triphenylphosphonium ([<Superscript>18</Superscript>F]FBnTP)

Purpose

The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[¹⁸F]fluorobenzyl-triphenylphosphonium ([¹⁸F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients.

Procedures

A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as well as chemical purity during several production runs (n = 24). The compound was purified by solid-phase extraction (SPE) with a Sep-Pak Plus Accell CM cartridge, thereby avoiding HPLC purification.

Results

Under optimized conditions, AY of 1.4–2.2 GBq of [¹⁸F]FBnTP were obtained from 9.4 to 12.0 GBq [¹⁸F]fluoride in 90–92 min (RCY = 28.6 ± 5.1 % with n = 3). Molar activities ranged from 80 to 99 GBq/μmol at the end of synthesis. RCP of final formulations was >?99 % at the end of synthesis and >?95 % after 8 h. With starting activities of 23.2–33.0 GBq, RCY decreased to 16.1 ± 0.4 % (n = 3). The main cause of the decline in RCY when high amounts of [¹⁸F]fluoride are used is radiolytic decomposition of [¹⁸F]FBnTP during SPE purification.

Conclusions

In initial attempts, the probe was synthesized with RCY <?0.6 % when starting activities up to 44.6 GBq were used. Rapid radiolysis of the intermediate 4-[¹⁸F]fluorobenzaldehyde and the final product [¹⁸F]FBnTP during purification was identified as the main cause for low yields in high-activity runs. Radiolytic decomposition was hindered by the addition of radical scavengers during synthesis, purification, and formulation, thereby improving AY and RCP. The formulated probe in injectable form was synthesized without the use of HPLC and passed all applicable quality control tests.

     

Quantification of Tau Load Using [<Superscript>18</Superscript>F]AV1451 PET

Purpose

The tau tracer [¹⁸F]AV1451, also known as flortaucipir, is a promising ligand for imaging tau accumulation in Alzheimer’s disease (AD). Most of the previous studies have quantified tau load using standardized uptake value ratios (SUVr) derived from a static [¹⁸F]AV1451 scan. SUVr may, however, be flow dependent and, especially for longitudinal studies, should be validated against a fully quantitative approach. The objective of this study was to identify the optimal tracer kinetic model for measuring tau load using [¹⁸F]AV1451.

Procedures

Following intravenous injection of 225 ± 16 MBq [¹⁸F]AV1451, 130 min dynamic PET scans were performed in five biomarker confirmed AD patients and five controls. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function. Next, regional time–activity curves were generated using PVElab software. These curves were analysed using several pharmacokinetic models.

Results

The reversible single tissue compartment model (1T2k_V_B) was the preferred model for all but one control. For AD patients, however, model preference shifted towards a reversible two tissue compartmental model (2T4k_V_B). The simplified reference tissue model (SRTM) derived binding potential (BP_ND) showed good correlation (AD: r ² = 0.87, slope = 1.06; controls: r ² = 0.87, slope = 0.86) with indirect plasma input binding (distribution volume ratio-1). Standardized uptake value ratios (80–100 min) correlated well with DVR (r ² = 0.93, slope = 1.07) and SRTM-derived BP_ND (r ² = 0.84, slope = 0.95). In addition, regional differences in tracer binding between subject groups in different tau-specific regions were observed.

Conclusions

Model preference of [¹⁸F]AV1451 appears to depend on subject status and, in particular, V_T. The relationship between model preference and V_T suggests that (higher) tau load may be reflected by a second tissue compartment. Nevertheless, consistent results can be obtained using a 2T4k_V_B model. In addition, SRTM can be used to derive BP_ND.

     

Applying Amide Proton Transfer MR Imaging to Hybrid Brain PET/MR: Concordance with Gadolinium Enhancement and Added Value to [<Superscript>18</Superscript>F]FDG PET

Purpose

The purpose of this study is to evaluate the diagnostic concordance and metric correlations of amide proton transfer (APT) imaging with gadolinium-enhanced magnetic resonance imaging (MRI) and 2-deoxy-2-[¹⁸F-]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET), using hybrid brain PET/MRI.

Procedures

Twenty-one subjects underwent brain gadolinium-enhanced [¹⁸F]FDG PET/MRI prospectively. Imaging accuracy was compared between unenhanced MRI, MRI with enhancement, APT-weighted (APTW) images, and PET based on six diagnostic criteria. Among tumors, the McNemar test was further used for concordance assessment between gadolinium-enhanced imaging, APT imaging, and [¹⁸F]FDG PET. As well, the relation of metrics between APT imaging and PET was analyzed by the Pearson correlation analysis.

Results

APT imaging and gadolinium-enhanced MRI showed superior and similar diagnostic accuracy. APTW signal intensity and gadolinium enhancement were concordant in 19 tumors (100 %), while high [¹⁸F]FDG avidity was shown in only 12 (63.2 %). For the metrics from APT imaging and PET, there was significant correlation for 13 hypermetabolic tumors (P < 0.05) and no correlation for the remaining six [¹⁸F]FDG-avid tumors.

Conclusions

APT imaging can be used to increase diagnostic accuracy with no need to administer gadolinium chelates. APT imaging may provide an added value to [¹⁸F]FDG PET in the evaluation of tumor metabolic activity during brain PET/MR studies.

     

<Superscript>11</Superscript>C-Acetate PET in the Evaluation of Brain Glioma: Comparison with <Superscript>11</Superscript>C-Methionine and <Superscript>18</Superscript>F-FDG-PET

PURPOSE: The aim of the study is to retrospectively investigate the usefulness of (11)C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with (11)C-methionine (MET) and 2-deoxy-2-(18)F-fluoro-D: -glucose (FDG). PROCEDURES: Fifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis. RESULTS: Sensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET. CONCLUSIONS: ACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.     

P-Glycoprotein,not BCRP,Limits the Brain Uptake of [<Superscript>18</Superscript>F]Mefway in Rodent Brain

Purpose

The aim of this study was to determine whether the brain uptake of [¹⁸F]Mefway is influenced by the action of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) in rodents.

Procedures

[¹⁸F]Mefway was applied to rats pharmacologically inhibited with tariquidar (TQD) and to genetically disrupted mice.

Results

Pretreatment of TQD results in 160 % higher hippocampal uptake compared with control rats. In genetically disrupted mice, a maximal brain uptake value of 3.2 SUV in the triple knockout mice (tKO, Mdr1a/b^(?/?)Bcrp1^(?/?)) was comparable to that of the double knockout mice (dKO, Mdr1a/b^(?/?)) and 2-fold those of the wild-type and Bcrp1^(?/?) knockout mice. The differences of binding values were statistically insignificant between control and experimental groups. The brain-to-plasma ratios for tKO mice were also two to five times higher than those for other groups.

Conclusions

[¹⁸F]Mefway is modulated by P-gp, and not by Bcrp in rodents.

     

[<Superscript>18</Superscript>F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice

Purpose

The association of Zika virus (ZIKV) infection and development of neurological sequelae require a better understanding of the pathogenic mechanisms causing severe disease. The purpose of this study was to evaluate the ability and sensitivity of positron emission tomography (PET) imaging using [¹⁸F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice.

Procedures

We assessed ZIKV-induced pathogenesis in wild-type C57BL/6 mice administered an antibody to inhibit type I interferon (IFN) signaling. [¹⁸F]DPA-714 PET imaging was performed on days 3, 6, and 10 post-infection (PI), and tissues were subsequently processed for histological evaluation, quantification of microgliosis, and detection of viral RNA by in situ hybridization (ISH).

Results

In susceptible ZIKV-infected mice, viral titers in the brain increased from days 3 to 10 PI. Over this span, these mice showed a two- to sixfold increase in global brain neuroinflammation using [¹⁸F]DPA-714 PET imaging despite limited, regional detection of viral RNA. No measurable increase in ionized calcium binding adaptor molecule 1 (Iba-1) expression was noted at day 3 PI; however, there was a modest increase at day 6 PI and an approximately significant fourfold increase in Iba-1 expression at day 10 PI in the susceptible ZIKV-infected group relative to controls.

Conclusions

The results of the current study demonstrate that global neuroinflammation plays a significant role in the progression of ZIKV infection and that [¹⁸F]DPA-714 PET imaging is a sensitive tool relative to histology for the detection of neuroinflammation. [¹⁸F]DPA-714 PET imaging may be useful in dynamically characterizing the pathology associated with neurotropic viruses and the evaluation of therapeutics being developed for treatment of infectious diseases.

     

Uptake of Radium-223 Dichloride and Early [<Superscript>18</Superscript>F]NaF PET Response Are Driven by Baseline [<Superscript>18</Superscript>F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients

Purpose

The purpose of this study is to identify predictive factors on baseline [¹⁸F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients.

Procedures

Analysis of 152 metastases was performed in six consecutive patients who underwent [¹⁸F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [¹⁸F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [¹⁸F]NaF [maximum standardized uptake value (SUV_max), SUV_mean, and lesion volume (V_18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUV_max and SUV_mean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [¹⁸F]NaF PET/CT. Total [¹⁸F]NaF uptake in metastases, defined as MATV × SUV_mean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment.

Results

Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUV_max and SUV_mean were better predictors of lesion response than V_18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUV_max and SUV_mean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUV_max (P = 0.002 and 0.007, respectively). A good correlation between total [¹⁸F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7 days after treatment (r = 0.72 and 0.77, P < 0.0001) was found.

Conclusions

SUV_max and SUV_mean on baseline [¹⁸F]NaF PET/CT are independent predictors of bone lesions’ response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.

     

Metabolic Brain Network Analysis of Hypothyroidism Symptom Based on [<Superscript>18</Superscript>F]FDG-PET of Rats

Purpose

Recent researches have demonstrated the value of using 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission tomography (PET) imaging to reveal the hypothyroidism-related damages in local brain regions. However, the influence of hypothyroidism on the entire brain network is barely studied. This study focuses on the application of graph theory on analyzing functional brain networks of the hypothyroidism symptom.

Procedures

For both the hypothyroidism and the control groups of Wistar rats, the functional brain networks were constructed by thresholding the glucose metabolism correlation matrices of 58 brain regions. The network topological properties (including the small-world properties and the nodal centralities) were calculated and compared between the two groups.

Results

We found that the rat brains, like human brains, have typical properties of the small-world network in both the hypothyroidism and the control groups. However, the hypothyroidism group demonstrated lower global efficiency and decreased local cliquishness of the brain network, indicating hypothyroidism-related impairment to the brain network. The hypothyroidism group also has decreased nodal centrality in the left posterior hippocampus, the right hypothalamus, pituitary, pons, and medulla. This observation accorded with the hypothyroidism-related functional disorder of hypothalamus-pituitary-thyroid (HPT) feedback regulation mechanism.

Conclusion

Our research quantitatively confirms that hypothyroidism hampers brain cognitive function by causing impairment to the brain network of glucose metabolism. This study reveals the feasibility and validity of applying graph theory method to preclinical [¹⁸F]FDG-PET images and facilitates future study on human subjects.

     

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [<Superscript>18</Superscript>F]FDG PET and acidoCEST MRI

Purpose

We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment.

Procedures

A standard 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1 day before treatment, 1 day after initiating daily treatment with metformin, and 7 days after initiating treatment. Longitudinal changes in SUV_max and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUV_max and pHe between metformin-treated and control groups were also evaluated.

Results

MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [¹⁸F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUV_max of the tumor model had a significant decrease after 7 days of treatment with metformin, as expected. The average tumor pHe decreased after 7 days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUV_max of the tumor model was not significantly different between the metformin-treated and control groups after 7 days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUV_max and pHe measurements significantly differed between the treatment group and control group on Day 7.

Conclusions

[¹⁸F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.

     

Quantitative Analysis of [<Superscript>18</Superscript>F]FMISO PET for Tumor Hypoxia: Correlation of Modeling Results with Immunohistochemistry

Purpose

Quantitative evaluation of tumor hypoxia based on H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO) positron emission tomography (PET) can deliver important information for treatment planning in radiotherapy. However, the merits and limitations of different analysis methods in revealing the underlying physiological feature are not clear. This study aimed to assess these quantitative analysis methods with the support of immunohistological data.

Procedures

Sixteen nude mice bearing xenografted human squamous cell carcinomas (FaDu or CAL-33) were scanned using 2-h dynamic [¹⁸F]FMISO PET. Tumors were resected and sliced, and the hypoxia marker pimonidazole was immunostained followed by H&E staining. The pimonidazole signal was segmented using a k-means clustering algorithm, and the hypoxic fraction (HF) was calculated as the hypoxic area/viable tumor-tissue-area ratio pooled over three tissue slices from the apical, center, and basal layers. PET images were analyzed using various methods including static analysis [standard uptake value (SUV), tumor-to-blood ratio (T/B), tumor-to-muscle ratio (T/M)] and kinetic modeling (Casciari αk _A , irreversible and reversible two-tissue compartment k ₃, Thorwarth w _A k ₃, Patlak K _i , Logan V _d , Cho K), and correlated with HF.

Results

No significant correlation was found for static analysis. A significant correlation between k ₃ of the irreversible two-tissue compartment model and HF was observed (r?=?0.61, p?=?0.01). The correlation between HF and αk _A of the Casciari model could be improved through reducing local minima by testing more sets of initial values (r?=?0.59, p?=?0.02) or by reducing the model complexity by fixing three parameters (r?=?0.63, p?=?0.0008).

Conclusions

With support of immunohistochemistry data, this study shows that various analysis methods for [¹⁸F]FMISO PET perform differently for assessment of tumor hypoxia. A better fitting quality does not necessarily mean a higher physiological correlation. Hypoxia PET analysis needs to consider both the mathematical stability and physiological fidelity. Based on the results of this study, preference should be given to the irreversible two-tissue compartment model as well as the Casciari model with reduced parameters.

     

Biodistribution and Radiation Dosimetry of [<Superscript>18</Superscript>F]Mefway in Humans

Purpose

[¹⁸F]Mefway is a positron emission tomography (PET) radioligand for quantification of the brain serotonin 1A (5-HT_1A) receptor density. The purpose of this study was to evaluate the radiation safety of [¹⁸F]Mefway in humans.

Procedures

Six healthy volunteers (three males and three females) were whole-body PET scanned for 114 min after injection of [¹⁸F]Mefway (226?±?35 MBq). Estimated radiation doses were determined by the OLINDA/EXM software.

Results

[¹⁸F]Mefway was safe and well tolerated by all subjects. Residence time ranges from 0 (gallbladder) to 0.822 h (urinary bladder wall). While the estimated radiation doses in the reproductive and blood-forming organs were below 13.35–22.87 μSv/MBq, radiation dose in the urinary bladder wall was 471 μSv/MBq. The mean effective dose was 40.23?±?6.63 μSv/MBq.

Conclusion

For a typical single injection of 185 MBq (5 mCi), the dose will result in 87.1 mSv for the urinary bladder wall. To reduce radiation burden, the bladder voiding can be used before [¹⁸F]Mefway PET scan.

     

Monitoring of Cardiac Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy with [<Superscript>18</Superscript>F]FDG MicroPET

Purpose

This study aims to analyze the left ventricular function parameters, scar load, and hypertrophy in a mouse model of pressure-overload left ventricular (LV) hypertrophy over the course of 8 weeks using 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) micro-positron emission tomography (microPET) imaging.

Procedures

LV hypertrophy was induced in C57BL/6 mice by transverse aortic constriction (TAC). Myocardial hypertrophy developed after 2–4 weeks. ECG-gated microPET scans with [¹⁸F]FDG were performed 4 and 8 weeks after surgery. The extent of fibrosis was measured by histopathologic analysis. LV function parameters and scar load were calculated using QGS®/QPS®. LV metabolic volume (LVMV) and percentage injected dose per gram were estimated by threshold-based analysis.

Results

The fibrotic tissue volume increased significantly from 4 to 8 weeks after TAC (?1.67 vs. 3.91  mm³; P = 0.044). There was a significant increase of the EDV (4 weeks: 54 ± 15 μl, 8 weeks: 79 ± 32 μl, P < 0.01) and LVMV (4 weeks: 222 ± 24 μl, 8 weeks: 276 ± 52 μl, P < 0.01) as well as a significant decrease of the LVEF (4 weeks: 56 ± 17 %, 8 weeks: 44 ± 20 %, P < 0.01). The increase of LVMV had a high predictive value regarding the amount of ex vivo measured fibrotic tissue (R = 0.905, P < 0.001). The myocardial metabolic defects increased within 4 weeks (P = 0.055) but only moderately correlated with the fibrosis volume (R = 0.502, P = 0.021). The increase in end-diastolic volume showed a positive correlation with the fibrosis at 8 weeks (R = 0.763, P = 0.017).

Conclusions

[¹⁸F]FDG-PET is applicable for serial in vivo monitoring of the TAC mouse model. Myocardial hypertrophy, the dilation of the left ventricle, and the decrease in LVEF could be reliably quantified over time, as well as the developing localized scar. The increase in volume over time is predictive of a high fibrosis load.

     

Investigation of cis-4-[<Superscript>18</Superscript>F]Fluoro-D-Proline Uptake in Human Brain Tumors After Multimodal Treatment

Purpose

Cis-4-[¹⁸F]fluoro-D-proline (D-cis-[¹⁸F]FPro) has been shown to pass the intact blood-brain barrier and to accumulate in areas of secondary neurodegeneration and necrosis in the rat brain while uptake in experimental brain tumors is low. This pilot study explores the uptake behavior of D-cis-[¹⁸F]FPro in human brain tumors after multimodal treatment.

Procedures

In a prospective study, 27 patients with suspected recurrent brain tumor after treatment with surgery, radiotherapy, and/or chemotherapy (SRC) were investigated by dynamic positron emission tomography (PET) using D-cis-[¹⁸F]FPro (22 high-grade gliomas, one unspecified glioma, and 4 metastases). Furthermore, two patients with untreated lesions were included (one glioblastoma, one reactive astrogliosis). Data were compared with the results of PET using O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) which detects viable tumor tissue. Tracer distribution, mean and maximum lesion-to-brain ratios (LBR_mean, LBR_max), and time-to-peak (TTP) of the time activity curve (TAC) of tracer uptake were evaluated. Final diagnosis was determined by histology (n?=?9), clinical follow-up (n?=?10), or by [¹⁸F]FET PET (n?=?10).

Results

D-cis-[¹⁸F]FPro showed high uptake in both recurrent brain tumors (n?=?11) and lesions classified as treatment-related changes (TRC) only (n?=?16) (LBR_mean 2.2?±?0.7 and 2.1?±?0.6, n.s.; LBR_max 3.4?±?1.2 and 3.2?±?1.3, n.s.). The untreated glioblastoma and the lesion showing reactive astrogliosis exhibited low D-cis-[¹⁸F]FPro uptake. Distribution of [¹⁸F]FET and D-cis-[¹⁸F]FPro uptake was discordant in 21/29 cases indicating that the uptake mechanisms are different.

Conclusion

The high accumulation of D-cis-[¹⁸F]FPro in pretreated brain tumors and TRC supports the hypothesis that tracer uptake is related to cell death. Further studies before and after therapy are needed to assess the potential of D-cis-[¹⁸F]FPro for treatment monitoring.

     

Quantification of Tumor Hypoxic Fractions Using Positron Emission Tomography with [<Superscript>18</Superscript>F]Fluoromisonidazole ([<Superscript>18</Superscript>F]FMISO) Kinetic Analysis and Invasive Oxygen Measurements

Purpose

The purpose of this study is to use dynamic [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) to compare estimates of tumor hypoxic fractions (HFs) derived by tracer kinetic modeling, tissue-to-blood ratios (TBR), and independent oxygen (pO₂) measurements.

Procedures

BALB/c mice with EMT6 subcutaneous tumors were selected for PET imaging and invasive pO₂ measurements. Data from 120-min dynamic [¹⁸F]FMISO scans were fit to two-compartment irreversible three rate constant (K ₁, k ₂, k ₃) and Patlak models (K _i). Tumor HFs were calculated and compared using K _i, k ₃, TBR, and pO₂ values. The clinical impact of each method was evaluated on [¹⁸F]FMISO scans for three non-small cell lung cancer (NSCLC) radiotherapy patients.

Results

HFs defined by TBR (≥1.2, ≥1.3, and ≥1.4) ranged from 2 to 85 % of absolute tumor volume. HFs defined by K _i (>0.004 ml min cm^?3) and k ₃ (>0.008 min^?1) varied from 9 to 85 %. HF quantification was highly dependent on metric (TBR, k ₃, or K _i) and threshold. HFs quantified on human [¹⁸F]FMISO scans varied from 38 to 67, 0 to 14, and 0.1 to 27 %, for each patient, respectively, using TBR, k ₃, and K _i metrics.

Conclusions

[¹⁸F]FMISO PET imaging metric choice and threshold impacts hypoxia quantification reliability. Our results suggest that tracer kinetic modeling has the potential to improve hypoxia quantification clinically as it may provide a stronger correlation with direct pO₂ measurements.

     

Preclinical Evaluation of 4-[<Superscript>18</Superscript>F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer

Purpose

Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[¹⁸F]Fluoroglutamine (4-[¹⁸F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression.

Procedures

In vivo microPET studies of 4-[¹⁸F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting.

Result

4-[¹⁸F]Fluoro-Gln uptake, but not 2-deoxy-2-[¹⁸F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[¹⁸F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues.

Conclusions

4-[¹⁸F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.