[<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.

     

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.

     

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.

     

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 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.

     

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.

     

Reduction of [<Superscript>18</Superscript>F]Fluoromisonidazole Uptake After Neoadjuvant Chemotherapy for Head and Neck Squamous Cell Carcinoma

Purpose  

The purpose of this study was to investigate the changes of tumor hypoxia as a result of neoadjuvant chemotherapy (NAC) by measuring the changes of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) uptake, as well as to look into the ability of [¹⁸F]FMISO PET to predict the NAC result.     

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.

     

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.

     

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.

     

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.

     

Al[<Superscript>18</Superscript>F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression

Purpose

Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist.

Procedures

T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[¹⁸F]. Al[¹⁸F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models.

Results

Labeling of Al[¹⁸F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58?±?5.3 % at the end of synthesis, based on fluoride-18 activity. Al[¹⁸F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[¹⁸F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[¹⁸F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors.

Conclusions

The simplicity of Al[¹⁸F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically.

     

[<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.

     

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.

     

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.

     

[<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.

     

Microvessel Density But Not Neoangiogenesis Is Associated with <Superscript>18</Superscript>F-FDG Uptake in Human Atherosclerotic Carotid Plaques

Introduction  

The vulnerable atherosclerotic lesion exhibits the proliferation of neovessels and inflammation. The imaging modality 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography (¹⁸FDG-PET) is considered for the identification of vulnerable plaques.     

Comparison of [<Superscript>11</Superscript>C]Choline ([<Superscript>11</Superscript>C]CHO) and [<Superscript>18</Superscript>F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model

Purpose

Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [¹⁸F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [¹¹C]Choline ([¹¹C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT).

Procedures

We carried out a dual-tracer small animal PET/CT study comparing [¹⁸F]Bombesin and [¹¹C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n?=?10) (PET/CT measurements of two [¹¹C]Choline mice could not be analyzed due to technical reasons). [¹⁸F]Bombesin and [¹¹C]CHO PET/CT imaging was performed about 3–4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [¹⁸F]Bombesin and 37 MBq [¹¹C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [¹⁸F]Bombesin and [¹¹C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4?×?4?×?4 mm³ volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used.

Results

The mean T/M ratio of [¹⁸F]Bombesin and [¹¹C]CHO was 6.54?±?2.49 and 1.35?±?0.30, respectively. The mean T/B ratio was 1.83?±?0.79 for [¹⁸F]Bombesin and 0.55?±?0.10 for [¹¹C]CHO. The T/M ratio as well as the T/B ratio for [¹⁸F]Bombesin were significantly higher compared to those for [¹¹C]CHO (p?<?0.001, respectively). Kidney and liver uptake was statistically significantly lower for [¹⁸F]Bombesin (K/B 3.41?±?0.81, L/B 1.99?±?0.38) compared to [¹¹C]CHO [K/B 7.91?±?1.85 (p?<?0.001), L/B 6.27?±?1.99 (p?<?0.001)]. The magnitudes of the time course of T/M and T/B ratios (T/M and T/B_dyn ratios) were statistically significantly different (showing a higher uptake of [¹⁸F]Bombesin compared to [¹¹C]CHO); additionally, also the change of the T/M and T/B ratios over time was significantly different between both tracers in the dynamic analysis (p?<?0.001, respectively). Furthermore, there was a statistically significantly different change of the K/B and L/B ratios over time between the two tracers in the dynamic analysis (p?=?0.026 and p?<?0.001, respectively).

Conclusions

[¹⁸F]Bombesin (BAY 86-4367) visually and semi-quantitatively outperforms [¹¹C]CHO in the PC-3 prostate cancer xenograft model. [¹⁸F]Bombesin tumor uptake was significantly higher compared to [¹¹C]CHO. [¹⁸F]Bombesin showed better imaging properties compared to the clinically utilized [¹¹C]CHO due to a higher tumor uptake as well as a lower liver and kidney uptake.

     

The Utility of [<Superscript>18</Superscript>F]DASA-23 for Molecular Imaging of Prostate Cancer with Positron Emission Tomography

Purpose

There is a strong, unmet need for superior positron emission tomography (PET) imaging agents that are able to measure biochemical processes specific to prostate cancer. Pyruvate kinase M2 (PKM2) catalyzes the concluding step in glycolysis and is a key regulator of tumor growth and metabolism. Elevation of PKM2 expression was detected in Gleason 8–10 tumors compared to Gleason 6–7 carcinomas, indicating that PKM2 may potentially be a marker of aggressive prostate cancer. We have recently reported the development of a PKM2-specific radiopharmaceutical [¹⁸F]DASA-23 and herein describe its evaluation in cell culture and preclinical models of prostate cancer.

Procedure

The cellular uptake of [¹⁸F]DASA-23 was evaluated in a panel of prostate cancer cell lines and compared to that of [¹⁸F]FDG. The specificity of [¹⁸F]DASA-23 to measure PKM2 levels in cell culture was additionally confirmed through the use of PKM2-specific siRNA. PET imaging studies were then completed utilizing subcutaneous prostate cancer xenografts using either PC3 or DU145 cells in mice.

Results

[¹⁸F]DASA-23 uptake values over 60-min incubation period in PC3, LnCAP, and DU145 respectively were 23.4?±?4.5, 18.0?±?2.1, and 53.1?±?4.6 % tracer/mg protein. Transient reduction in PKM2 protein expression with siRNA resulted in a 50.1 % reduction in radiotracer uptake in DU145 cells. Small animal PET imaging revealed 0.86?±?0.13 and 1.6?±?0.2 % ID/g at 30 min post injection of radioactivity in DU145 and PC3 subcutaneous tumor bearing mice respectively.

Conclusion

Herein, we evaluated a F-18-labeled PKM2-specific radiotracer, [¹⁸F]DASA-23, for the molecular imaging of prostate cancer with PET. [¹⁸F]DASA-23 revealed rapid and extensive uptake levels in cellular uptake studies of prostate cancer cells; however, there was only modest tumor uptake when evaluated in mouse subcutaneous tumor models.