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>18</Superscript>F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling

Purpose

[¹⁸F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [¹⁸F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [¹⁸F]fluorocholine PET/CT before tumor resection.

Procedures

Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio. For clinical-radiopathologic correlation, HCC profiles were reduced to two orthogonal principal component factors (PCF1 and PCF2) accounting for 80 % of total profile variation.

Results

Tissues from 31 HCC patients and 4 intrahepatic cholangiocarcinoma (ICC) patients were analyzed, revealing significantly higher levels of phosphocholine, CDP-choline, and highly saturated phosphatidylcholine species in HCC tumors relative to adjacent liver and ICC tumors. Significant loading values for PCF1 corresponded to phosphatidylcholines containing poly-unsaturated fatty acids while PCF2 corresponded only to highly saturated phosphatidylcholines. Only PCF2 correlated significantly with HCC tumor-to-liver [¹⁸F]fluorocholine uptake ratio (ρ = 0.59, p < 0.0005). Sensitivity for all tumors based on an abnormal [¹⁸F]fluorocholine uptake ratio was 93 % while sensitivity for HCC based on increased tumor [¹⁸F]fluorocholine uptake was 84 %, with lower levels of highly saturated phosphatidylcholines in tumors showing low [¹⁸F]fluorocholine uptake.

Conclusion

Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [¹⁸F]fluorocholine PET/CT can serve to identify these lipogenic tumors, its imperfect diagnostic sensitivity implies metabolic heterogeneity across HCC and a weaker lipogenic phenotype in some tumors.

     

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.

     

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 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.

     

Biodistribution and Radiation Dosimetry of the <Emphasis Type="Italic">Enterobacteriaceae</Emphasis>-Specific Imaging Probe [<Superscript>18</Superscript>F]Fluorodeoxysorbitol Determined by PET/CT in Healthy Human Volunteers

Purpose

[¹⁸F]fluorodeoxysorbitol ([¹⁸F]FDS) is the first radiopharmaceutical specific for a category of bacteria and has the potential to specifically detect Enterobacteriaceae infections. The purpose of this study was to testify the safety and investigate the biodistribution and radiation dosimetry of [¹⁸F]FDS in healthy human bodies.

Procedures

Six healthy subjects were intravenously injected with 320–520 MBq [¹⁸F]FDS. On each subject, 21 whole-body emission scans and a brain scan were conducted at settled time points within the next 4 h. Residence time for each source organ was determined by multi-exponential regression. Absorbed doses for target organs and effective dose were calculated via OLINDA/EXM.

Results

No adverse events due to [¹⁸F]FDS injection were observed in the study. The tracer was cleared rapidly from the blood pool through the urinary system. A small portion was cleared into the gut through the hepatobiliary system. The effective dose (ED) was estimated to be 0.021?±?0.001 mSv/MBq. The organ receiving the highest absorbed dose was the urinary bladder wall (0.25?±?0.03 mSv/MBq).

Conclusions

[¹⁸F]FDS is safe and well tolerated. The effective dose was comparable to that of other F-18 labeled radiotracers. [¹⁸F]FDS is suitable for human use from a radiation dosimetry perspective.

     

Preclinical Evaluation of [<Superscript>18</Superscript>F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer

Purpose

Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [¹⁸F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [¹⁸F]THK-5105 enantiomers.

Procedures

Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay

Results

The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (S)-[¹⁸F]THK-5105 has slower dissociation from tau than (R)-[¹⁸F]THK-5105. Biodistribution assays indicated that (S)-[¹⁸F]THK-5105 eliminated faster from the mouse brains and blood compared with (R)-[¹⁸F]THK-5105.

Conclusion

(S)-[¹⁸F]THK-5105 could be more suitable than (R)-enantiomer for a tau imaging agent.

     

<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Radiofluorinated Caspase-3/7 Inhibitors as Radiotracers for Apoptosis Imaging and Comparison with [<Superscript>18</Superscript>F]ML-10 in a Stroke Model in the Rat

Purpose

The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.

Procedures

In vivo characteristics of isatins [¹⁸F]-2 and [¹⁸F]-3 were studied and compared by μPET to previously described 1-[4-(2-[¹⁸F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([¹⁸F]-1) and to 2-(5-[¹⁸F]fluoropentyl)-2-methyl-malonic acid ([¹⁸F]ML-10) used as a reference radiotracer in a rat stroke model.

Results

[¹⁸F]-2 and [¹⁸F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [¹⁸F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [¹⁸F]-1 after 45 min. No differences were observed for [¹⁸F]ML-10.

Conclusions

Radiolabelled isatins are more promising radiotracers to image apoptosis than [¹⁸F]ML-10 in this stroke animal model without craniectomy. In particular, [¹⁸F]-1 presented significant uptake in apoptotic area 45 min after administration

     

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.

     

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.

     

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.

     

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.

     

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.

     

[<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.

     

Response Monitoring with [<Superscript>18</Superscript>F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases

Purpose

The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases.

Procedures

Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [¹⁸F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression.

Results

5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [¹⁸F]FLT SUV_mean and SUV_max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV_max at days ?1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [¹⁸F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADC_mean) did not change in 5-FU-treated rats compared to untreated rats.

Conclusion

This study suggests that 5-FU treatment induces a flare in [¹⁸F]FLT uptake of responsive CC531 tumors in the liver, while the ADC_mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [¹⁸F]FLT PET can discriminate between disease progression and treatment response.

     

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.

     

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.

     

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.