PET Imaging Analysis of Vitamin B<Subscript>1</Subscript> Kinetics with [<Superscript>11</Superscript>C]Thiamine and its Derivative [<Superscript>11</Superscript>C]Thiamine Tetrahydrofurfuryl Disulfide in Rats

Purpose

Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart.

Procedures

Positron emission tomography (PET) imaging with [¹¹C]thiamine and [¹¹C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography.

Results

Accumulation of [¹¹C]TTFD was significantly higher than that of [¹¹C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [¹¹C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [¹¹C]thiamine-injected group.

Conclusions

PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [¹¹C]thiamine and [¹¹C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

     

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[<Superscript>11</Superscript>C]Rolipram

Purpose

Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates.

Procedures

Positron emission tomography (PET) measurements with (R)-[¹¹C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V_T) and V_T/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.

Results

The brain uptake of (R)-[¹¹C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/kg of roflumilast, regardless of outcome measures, V_T or V_T/fp.

Conclusions

This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

     

Human Radiation Dosimetry of [<Superscript>18</Superscript>F]AV-1451(T807) to Detect Tau Pathology

Purpose

[¹⁸F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [¹⁸F]AV-1451 in humans.

Procedures

Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [¹⁸F]AV-1451 (268?±?31 MBq). Radiation doses were estimated using the OLINDA/EXM software.

Results

The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47?±?3.59 μSv/MBq.

Conclusions

A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [¹⁸F]AV-1451 could be used in multiple PET scans of the same subject per year.

     

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.

     

[<Superscript>11</Superscript>C]acetate PET Imaging is not Always Associated with Increased Lipogenesis in Hepatocellular Carcinoma in Mice

Purpose

Altered metabolism, including increased glycolysis and de novo lipogenesis, is one of the hallmarks of cancer. Radiolabeled nutrients, including glucose and acetate, are extensively used for the detection of various tumors, including hepatocellular carcinomas (HCCs). High signal of [¹¹C]acetate positron emission tomography (PET) in tumors is often considered to be associated with increased expression of fatty acid synthase (FASN) and increased de novo lipogenesis in tumor tissues. Defining a subset of tumors with increased [¹¹C]acetate PET signal and thus increased lipogenesis was suggested to help select a group of patients, who may benefit from lipogenesis-targeting therapies.

Procedures

To investigate whether [¹¹C]acetate PET imaging is truly associated with increased de novo lipogenesis along with hepatocarcinogenesis, we performed [¹¹C]acetate PET imaging in wild-type mice as well as two mouse HCC models, induced by myrAKT/Ras^V12 (AKT/Ras) and PIK3CA^1047R/c-Met (PI3K/Met) oncogene combinations. In addition, we analyzed FASN expression and de novo lipogenesis rate in these mouse liver tissues.

Results

We found that while HCCs induced by AKT/Ras co-expression showed high levels of [¹¹C]acetate PET signal compared to normal liver, HCCs induced by PI3K/Met overexpression did not. Intriguingly, elevated FASN expression and increased de novo lipogenesis rate were observed in both AKT/Ras and PI3K/Met HCCs.

Conclusion

Altogether, our study suggests that [¹¹C]acetate PET imaging can be a useful tool for imaging of a subset of HCCs. However, at molecular level, the increased [¹¹C]acetate PET imaging is not always associated with increased FASN expression or de novo lipogenesis.

     

Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [<Superscript>18</Superscript>F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation

Purpose

To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.

Procedures

Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n?=?19) were delineated twice, once on PET and once on CT images.

Results

Sixty-three features showed an intraclass correlation coefficient?≥?0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).

Conclusions

The majority of features in NSCLC [¹⁸F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.

     

[<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.

     

Assessing Glomerular Filtration in Small Animals Using [<Superscript>68</Superscript>Ga]DTPA and [<Superscript>68</Superscript>Ga]EDTA with PET Imaging

Purpose

Determining the glomerular filtration rate (GFR) is essential for clinical medicine but also for pre-clinical animal studies. Functional imaging using positron emission tomography (PET) allows repetitive almost non-invasive measurements. The aim of the study was the development and evaluation of easily synthesizable PET tracers for GFR measurements in small animals.

Procedures

Diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) were labeled with Ga-68. The binding to blood cells and plasma proteins was tested in vitro. The distribution of the tracers in rats was analyzed by PET imaging and ex vivo measurements. From the time-activity-curve of the blood compartment (heart) and the total tracer mass excreted by the kidney, the GFR was calculated. These values were compared directly with the inulin clearance in the same animals.

Results

Both tracers did not bind to blood cells. [⁶⁸Ga]DPTA but not [⁶⁸Ga]EDTA showed strong binding to plasma proteins. For this reason, [⁶⁸Ga]DPTA stayed much longer in the blood and only 30 % of the injected dose was eliminated by the kidney within 60 min whereas the excretion of [⁶⁸Ga]EDTA was 89 ± 1 %. The calculated GFR using [⁶⁸Ga]EDTA was comparable to the measured inulin clearance in the same animal. Using [⁶⁸Ga]-DPTA, the measurements led to values which were 80 % below the normal GFR. The results also revealed that definition of the volume of interest for the blood compartment affects the calculation and may lead to a slight overestimation of the GFR.

Conclusions

[⁶⁸Ga]EDTA is a suitable tracer for GFR calculation from PET imaging in small animals. It is easy to be labeled, and the results are in good accordance with the inulin clearance. [⁶⁸Ga]DTPA led to a marked underestimation of GFR due to its strong binding to plasma proteins and is therefore not an appropriate tracer for GFR measurements.

     

Radiation Dosimetry of a Novel Adenosine A<Subscript>2A</Subscript> Receptor Radioligand [<Superscript>11</Superscript>C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Purpose

[¹¹C]Preladenant was developed as a novel adenosine A_2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [¹¹C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats.

Procedures

Male Wistar rats (n?=?35) were i.v. injected with [¹¹C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1.

Results

PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6–27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors.

Conclusions

The ED of [¹¹C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [¹¹C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

     

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.

     

Evaluation of PET Imaging Performance of the TSPO Radioligand [<Superscript>18</Superscript>F]DPA-714 in Mouse and Rat Models of Cancer and Inflammation

Purpose

Many radioligands have been explored for imaging the 18-kDa translocator protein (TSPO), a diagnostic and therapeutic target for inflammation and cancer. Here, we investigated the TSPO radioligand [¹⁸F]DPA-714 for positron emission tomography (PET) imaging of cancer and inflammation.

Procedures

[¹⁸F]DPA-714 PET imaging was performed in 8 mouse and rat models of breast and brain cancer and 4 mouse and rat models of muscular and bowel inflammation.

Results

[¹⁸F]DPA-714 showed different uptake levels in healthy organs and malignant tissues of mice and rats. Although high and displaceable [¹⁸F]DPA-714 binding is observed ex vivo, TSPO-positive PET imaging of peripheral lesions of cancer and inflammation in mice did not show significant lesion-to-background signal ratios. Slower [¹⁸F]DPA-714 metabolism and muscle clearance in mice compared to rats may explain the elevated background signal in peripheral organs in this species.

Conclusion

Although TSPO is an evolutionary conserved protein, inter- and intra-species differences call for further exploration of the pharmacological parameters of TSPO radioligands.

     

Evaluating [<Superscript>11</Superscript>C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

Purpose

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that affects an increasing number of patients. High comorbidity is observed between UC and other diseases in which inflammation may be involved, including brain diseases such as cognitive impairment, mental disorders, anxiety, and depression. To investigate the increased occurrence of these brain diseases in patients with UC, non-invasive methods for monitoring peripheral and central inflammation could be applied. Therefore, the goal of this study is to assess the feasibility of monitoring gut and brain inflammation in a rat model of chemically induced colitis by positron emission tomography (PET) with [¹¹C]PBR28, a tracer targeting the translocator protein (TSPO), which is upregulated when microglia and macrophages are activated.

Procedures

Colitis was induced in rats by intra-rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Rats with colitis and healthy control animals were subjected to [¹¹C]PBR28 PET of the abdomen followed by ex vivo biodistribution in order to assess whether inflammation in the gut could be detected. Another group of rats with colitis underwent repetitive [¹¹C]PBR28 PET imaging of the brain to investigate the development of neuroinflammation.

Results

Eleven days after TNBS injection, ex vivo biodistribution studies demonstrated increased [¹¹C]PBR28 uptake in the inflamed cecum and colon of rats with colitis as compared to healthy controls, whereas PET imaging did not show any difference between groups at any time. Similarly, repetitive PET imaging of the brain did not reveal any neuroinflammation induced by the TNBS administration in the colon. In contrast, significantly increased [¹¹C]PBR28 uptake in cerebellum could be detected in ex vivo biodistribution studies on day 11.

Conclusion

Inflammation in both the gut and the brain of rats with chemically induced colitis was observed by ex vivo biodistribution. However, these effects could not be detected by [¹¹C]PBR28 PET imaging in our colitis model, which is likely due to spill-over effects and insufficient resolution of the PET camera.

     

PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [<Superscript>11</Superscript>C]PBR28

Purpose

Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [¹¹C]PBR28 under thermoneutral conditions.

Procedures

In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [¹¹C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60–90 min after the injection of the tracer.

Results

[¹¹C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [¹¹C]PBR28 signal in BAT depots. The average (± SD) SUV_(mean) and SUV_max for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV_(mean) for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively.

Conclusions

In this brief article, we provide the first evidence suggesting that [¹¹C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.

     

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.

     

[<Superscript>89</Superscript>Zr]Trastuzumab: Evaluation of Radiation Dosimetry,Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer

Purpose

The purpose of the present study is to evaluate safety, human radiation dosimetry, and optimal imaging time of [⁸⁹Zr]trastuzumab in patients with HER2-positive breast cancer.

Procedures

Twelve women with HER2-positive breast cancer underwent [⁸⁹Zr]trastuzumab positron emission tomography (PET)/X-ray computed tomography (CT) twice within 7 days post-injection. Biodistribution data from whole-torso PET/CT images and organ time-activity curves were created using data from all patients. Human dosimetry was calculated using OLINDA with the adult female model.

Results

High-quality images and the greatest tumor-to-nontumor contrast were achieved with images performed 5?±?1 day post-injection. Increased [⁸⁹Zr]trastuzumab uptake was seen in at least one known lesion in ten patients. The liver was the dose-limiting organ (retention of ～12 % of the injected dose and average dose of 1.54 mSv/MBq). The effective dose was 0.47 mSv/MBq. No adverse effects of [⁸⁹Zr]trastuzumab were encountered.

Conclusion

[⁸⁹Zr]trastuzumab was safe and optimally imaged at least 4 days post-injection. The liver was the dose-limiting organ.

     

Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [<Superscript>11</Superscript>C]Raclopride in Non-human Primates

Purpose

Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BP_ND) of [¹¹C]raclopride in NHP.

Procedures

Three cynomolgus monkeys underwent two to three PET measurements with [¹¹C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BP_ND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.

Results

In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = ? 0.79, p = 0.03), but not with BP_ND (ρ = ? 0.25, p = 0.55).

Conclusions

These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BP_ND in consecutive PET measurements.

     

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.

     

Quantitative [<Superscript>18</Superscript>F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Purpose

Evaluation of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.

Procedures

Mice with BT474, HER2+ tumors, were imaged with [¹⁸F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.

Results

[¹⁸F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P?<?0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P?<?0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r ² ?=?0.85).

Conclusions

[¹⁸F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.

     

PSMA-Based [<Superscript>18</Superscript>F]DCFPyL PET/CT Is Superior to Conventional Imaging for Lesion Detection in Patients with Metastatic Prostate Cancer

Purpose

Current standard of care conventional imaging modalities (CIM) such as X-ray computed tomography (CT) and bone scan can be limited for detection of metastatic prostate cancer and therefore improved imaging methods are an unmet clinical need. We evaluated the utility of a novel second-generation low molecular weight radiofluorinated prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer, [¹⁸F]DCFPyL, in patients with metastatic prostate cancer.

Procedures

Nine patients with suspected prostate cancer recurrence, eight with CIM evidence of metastatic prostate cancer and one with biochemical recurrence, were imaged with [¹⁸F]DCFPyL PET/CT. Eight of the patients had contemporaneous CIM for comparison. A lesion-by-lesion comparison of the detection of suspected sites of metastatic prostate cancer was carried out between PET and CIM. Statistical analysis for estimated proportions of inter-modality agreement for detection of metastatic disease was calculated accounting for intra-patient correlation using general estimating equation (GEE) intercept-only regression models.

Results

One hundred thirty-nine sites of PET positive [¹⁸F]DCFPyL uptake (138 definite, 1 equivocal) for metastatic disease were detected in the eight patients with available comparison CIM. By contrast, only 45 lesions were identified on CIM (30 definite, 15 equivocal). When lesions were negative or equivocal on CIM, it was estimated that a large portion of these lesions or 0.72 (95 % confidence interval (CI) 0.55–0.84) would be positive on [¹⁸F]DCFPyL PET. Conversely, of those lesions negative or equivocal on [¹⁸F]DCFPyL PET, it was estimated that only a very small proportion or 0.03 (95 % CI 0.01–0.07) would be positive on CIM. Delayed 2-h-post-injection time point PET yielded higher tumor radiotracer uptake and higher tumor-to-background ratios than an earlier 1-h-post-injection time point.

Conclusions

A novel PSMA-targeted PET radiotracer, [¹⁸F]DCFPyL, was able to a large number of suspected sites of prostate cancer, many of which were occult or equivocal by CIM. This study provides strong preliminary evidence for the use of this second-generation PSMA-targeted PET radiotracer for detection of metastatic prostate cancer and lends further support for the importance of PSMA-targeted PET imaging in prostate cancer.