Electrophilic Addition of Chlorine Monofluoride for PET tracers

Purpose

We have studied the utility of [¹⁸F]ClF electrophilic addition to the carbon–carbon double bond of analogues of a model positron emission tomography (PET) tracer, [¹⁸F]EF5. The consequence of simultaneous chlorine/fluorine addition on lipophilicity and biological activity of the molecule is evaluated.

Procedures

Post-target produced [¹⁸F]F₂ was reacted with Cl₂ to produce [¹⁸F]ClF, which was used in electrophilic addition.

Results

[¹⁸F]ClF was produced and used to label chlorinated analogues of [¹⁸F]EF5. The chlorinated analogues, [¹⁸F]EF4Cl_a and [¹⁸F]EF4Cl_b, were synthesized simultaneously. The in vivo uptake of the analogues compared well with [¹⁸F]EF5 uptake in tumor-bearing mice.

Conclusion

[¹⁸F]ClF is a suitable labeling reagent for electrophilic addition to double bonds of PET tracers. The results show that the modification of the pentafluoro group of [¹⁸F]EF5 by monofluorine-for-chlorine exchange affected the lipophilicity, but the hypoxia avidity of these molecules was not apparently altered.     

Comparison of Hypermetabolic and Hypoxic Volumes Delineated on [18F]FDG and [18F]Fluoromisonidazole PET/CT in Non-small-cell Lung Cancer Patients

Purpose

The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small-cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. 2-Deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) and [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) (hypoxia) uptake on pre-radiotherapy positron emission tomography (PET)/X-ray computed tomography (CT) have been independently reported to identify intratumor subvolumes at higher risk of relapse after radiotherapy. We have compared the [¹⁸F]FDG and [¹⁸F]FMISO volumes defined by PET/CT in NSCLC patients included in a prospective study.

Procedures

Thirty-four patients with non-resectable lung cancer underwent [¹⁸F]FDG and [¹⁸F]FMISO PET/CT before (pre-RT) and during radiotherapy (around 42 Gy, per-RT). The criteria were to delineate 40 % and 90 % SUVmax thresholds on [¹⁸F]FDG PET/CT (metabolic volumes), and SUV >?1.4 on pre-RT [¹⁸F]FMISO PET/CT (hypoxic volume). The functional volumes were delineated within the tumor volume as defined on co-registered CTs.

Results

The mean pre-RT and per-RT [¹⁸F]FDG volumes were not statistically different (30.4 cc vs 22.2; P?=?0.12). The mean pre-RT SUVmax [¹⁸F]FDG was higher than per-RT SUVmax (12.7 vs 6.5; P?<?0.0001). The mean [¹⁸F]FMISO SUVmax and volumes were 2.7 and 1.37 cc, respectively. Volume-based analysis showed good overlap between [¹⁸F]FDG and [¹⁸F]FMISO for all methods of segmentation but a poor correlation for Jaccard or Dice Indices (DI). The DI maximum was 0.45 for a threshold at 40 or 50 %.

Conclusion

The correlation between [¹⁸F]FDG and [¹⁸F]FMISO uptake is low in NSCLC, making it possible to envisage different management strategies as the studies in progress show.

     

Syntheses and preliminary evaluation of [18F]AlF‐NOTA‐G‐TMTP1 for PET imaging of high aggressive hepatocellular carcinoma

The goal of this study is to evaluate a new ¹⁸F‐labeled imaging agent for diagnosing high metastatic (aggressive) hepatocellular carcinoma using positron emission tomography (PET). The new ¹⁸F‐labeled imaging agent [¹⁸F]AlF‐NOTA‐G‐TMTP1 was synthesized and radiolabeled with ¹⁸F using NOTA‐AlF chelation method. The tumor‐targeting characteristics of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was assessed in HepG2, SMCC‐7721, HCC97L and HCCLM3 xenografts. The total synthesis time was about 20 min with radiochemical yield of 25 ± 6%. The specific activity was about 11.1–14.8 GBq/µmol at the end of synthesis based on the amount of peptide used and the amount of radioactivity trapped on the C₁₈ column. The log P value of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was ‐3.166 ± 0.022. [¹⁸F]AlF‐NOTA‐G‐TMTP1 accumulated in SMCC‐7721 and HCCLM3 tumors (high metastatic potential) in vivo and result in tumor/muscle (T/M) ratios of 4.5 ± 0.3 and 4.7 ± 0.2 (n = 4) as measured by PET at 40 min post‐injection (p.i.). Meanwhile, the tumor/muscle (T/M) ratios of HepG2 and HCC97L tumors (low metastatic potential) were1.6 ± 0.3 and 1.8 ± 0.4. The tumor uptake of [¹⁸F]AlF‐NOTA‐G‐TMTP1 could be inhibited 61.9% and 57.6% by unlabeled G‐TMTP1 in SMCC‐7721 and HCCLM3 xenografts at 40 min p.i., respectively. Furthermore, [¹⁸F]AlF‐NOTA‐G‐TMTP1 showed pretty low activity in the liver and intestines in all tumor bearing mice, such in vivo distribution pattern would be advantageous for the detection of hepatic carcinoma. Overall, [¹⁸F]AlF‐NOTA‐G‐TMTP1 may specifically target high metastatic or/and aggressive hepatocellular carcinoma with low background activity and, therefore, holds the potential to be used as an imaging agent for detecting tumor lesions within the liver area. Copyright © 2016 John Wiley & Sons, Ltd.     

PET/CT to detect adverse reactions to metal debris in patients with metal‐on‐metal hip arthroplasty: an exploratory prospective study

Metal‐on‐metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2‐deoxy‐2‐[¹⁸F]fluoro‐d ‐glucose ([¹⁸F]FDG) and [⁶⁸Ga]Gallium citrate ([⁶⁸Ga]Citrate) PET/CT in ARMD patients. [¹⁸F]FDG and [⁶⁸Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUV_max) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence‐magnetic resonance imaging (MARS‐MRI). Periprosthetic [¹⁸F]FDG uptake was observed in 15 of 16 hips, [⁶⁸Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUV_max of [¹⁸F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0·009 for [¹⁸F]FDG and P = 0·217 for [⁶⁸Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUV_max as detected by preoperative [¹⁸F]FDG (P = 0·039), but not by [⁶⁸Ga]Citrate (P = 0·301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [¹⁸F]FDG.     

Semiautomated Radiosynthesis and Biological Evaluation of [<Superscript>18</Superscript>F]FEAU: A Novel PET Imaging Agent for <Emphasis Type="Italic">HSV1-tk/sr39tk</Emphasis> Reporter Gene Expression

2′-Deoxy-2′-[¹⁸F]fluoro-5-ethyl-1-β-d-arabinofuranosyluracil ([¹⁸F]FEAU) is a promising radiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [¹⁸F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [¹⁸F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means ± SD. Radiofluorination (33 ± 8%; n = 4), bromination (85 ± 8%; n = 4), coupling reaction (83 ± 6%; n = 4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [¹⁸F]FEAU β-anomer in 5 ± 1% overall yield (n = 3 runs) after ~5.5 h and a β/α-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.3 Ci/μmol (48 GBq/μmol), respectively. In cell culture, [¹⁸F]FEAU showed significantly (P < 0.05) higher accumulation in C6 cells expressing HSV1-tk/sr39tk as compared to wild-type C6 cells. Furthermore, [¹⁸F]FEAU showed slightly higher accumulation than 9-[4-[¹⁸F]fluoro-3-(hydroxymethyl)butylguanine ([¹⁸F]FHBG) in cells expressing HSV1-tk (P < 0.05), whereas [¹⁸F]FHBG showed significantly higher (P < 0.05) accumulation than [¹⁸F]FEAU in HSV1-sr39tk-expressing cells. micro-PET imaging of mice carrying tumor xenografts of C6 cells stably expressing HSV1-tk or HSV1-sr39tk are consistent with the cell uptake results. The [¹⁸F]FEAU mouse images also showed very low gastrointestinal signal with predominant renal clearance as compared to [¹⁸F]FHBG. The routine radiosynthesis of [¹⁸F]FEAU was successfully semiautomated using a commercial module along with customized equipment to provide the β-anomer in modest yields. Although further studies are needed, early results also suggest [¹⁸F]FEAU is a promising PET radiotracer for monitoring HSV1-tk reporter gene expression.     

The Effect of Insulin on the Intracellular Distribution of 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic Acid in Rats

Purpose The aim of this study was to determine the effect of hyperinsulinemia on myocardial and hepatic distribution and metabolism of 14(R,S)-[¹⁸F]fluoro-6-thia-heptadecanoic acid ([¹⁸F]FTHA).Procedures Mitochondrial retention and intracellular lipid incorporation of [¹⁸F]FTHA were compared to that of [¹⁴C]-2-bromopalmitate or [¹⁴C]palmitate during hyperinsulinemic clamp vs. saline infusion in male Wistar rats.Results Mitochondrial ¹⁸F activity was increased in the heart (1.7 ± 0.4 vs. 0.5 ± 0.1% ID/g, P < 0.05), whereas it was reduced in the liver (1.1 ± 0.3 vs. 1.8 ± 0.4% ID/g, P < 0.05) during insulin vs. saline infusion, respectively. Mitochondrial [¹⁴C]-2-bromopalmitate activity was affected by insulin in a similar way in both tissues. The fractional esterification of [¹⁸F]FTHA into triglycerides was impaired compared to [¹⁴C]palmitate in both tissues, and [¹⁸F]FTHA was insensitive to the shift of esterification of fatty acids into complex lipids in response to insulin.Conclusions [¹⁸F]FTHA is sensitive to insulin-induced modifications of free fatty acid oxidative metabolism in rats but is insensitive to changes in nonoxidative fatty acid metabolism.     

Quantitative 1H MRI, 19F MRI,and 19F MRS of cell‐internalized perfluorocarbon paramagnetic nanoparticles

In vivo molecular imaging with targeted MRI contrast agents will require sensitive methods to quantify local concentrations of contrast agent, enabling not only imaging‐based recognition of pathological biomarkers but also detection of changes in expression levels as a consequence of disease development, therapeutic interventions or recurrence of disease. In recent years, targeted paramagnetic perfluorocarbon emulsions have been frequently applied in this context, permitting high–resolution ¹H MRI combined with quantitative ¹⁹F MR imaging or spectroscopy, under the assumption that the fluorine signal is not altered by the local tissue and cellular environment. In this in vitro study we have investigated the ¹⁹F MR–based quantification potential of a paramagnetic perfluorocarbon emulsion conjugated with RGD–peptide to target the cell–internalizing α_νβ₃–integrin expressed on endothelial cells, using a combination of ¹H MRI, ¹⁹F MRI and ¹⁹F MRS. The cells took up the targeted emulsion to a greater extent than nontargeted emulsion. The targeted emulsion was internalized into large 1–7 µm diameter vesicles in the perinuclear region, whereas nontargeted emulsion ended up in 1–4 µm diameter vesicles, which were more evenly distributed in the cytoplasm. Association of the targeted emulsion with the cells resulted in different proton longitudinal relaxivity values, r₁, for targeted and control nanoparticles, prohibiting unambiguous quantification of local contrast agent concentration. Upon cellular association, the fluorine R₁ was constant with concentration, while the fluorine R₂ increased nonlinearly with concentration. Even though the fluorine relaxation rate was not constant, the ¹⁹F MRI and ¹⁹F MRS signals for both targeted nanoparticles and controls were linear and quantifiable as function of nanoparticle concentration. Copyright © 2010 John Wiley & Sons, Ltd.     

Erythrocytes labeled with [18F]SFB as an alternative to radioactive CO for quantification of blood volume with PET

Inhaled radioactive CO is currently the tracer of choice for blood volume quantification by positron emission tomography (PET). This measurement is of great interest for several clinical and research applications. However, owing to the short half‐life of the radiolabeled CO, it can only be used in centers equipped with a cyclotron. In the present work, we propose an alternative method to label the red blood cells with [¹⁸F] in order to obtain blood volume measurements by PET. The use of the radioactive synthon [¹⁸F] N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) was evaluated for erythrocyte labeling and PET blood volume imaging. The images provided by [¹⁸F]SFB labeled erythrocytes were compared with those obtained with inhaled [¹¹C]CO. Blood volumes obtained with [¹⁸F]SFB labeled erythrocytes were similar to those obtained with [¹¹C]CO in all of the evaluated organs with the exception of spleen, which presented lower uptake with this method. Since the [¹⁸F]‐SFB binds irreversibly to red blood cells, in vivo stability of the radiolabel was higher compared with the [¹¹C]CO method. Additionally, owing to the longer half‐life and the shorter positron range of [¹⁸F], the image quality was also higher with the [¹⁸F]SFB radiolabeled erythrocytes. The labeling of red blood with [¹⁸F]SFB represents an advantageous alternative to radioactive CO for blood volume measurement by PET and cardiovascular isotopic imaging. Copyright © 2013 John Wiley & Sons, Ltd.     

Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: Effects of the novel P-glycoprotein inhibitor tariquidar

We used microPET to map the dose–response to the novel P-glycoprotein (P-gp) inhibitor tariquidar (TQD) of the initial influx of the P-gp substrate [¹⁸F]-MPPF in rat brain, and to test for effects of P-gp inhibition on the subsequent binding of [¹⁸F]-MPPF to serotonin 5-HT_1A receptors. Summation maps of [¹⁸F]-MPPF uptake during the first 100 seconds after intravenous injection were calculated in groups of rats with vehicle (glucose 5%) pretreatment, or following pretreatment with TQD at doses of 5, 15, or 30 mg/kg. The early summation image (K₁-weighted), were validated as a surrogate marker for the physiological blood–brain clearance (K₁; ml g^? 1 min^? 1) by linear graphic analysis of the unidirectional blood–brain clearance relative to an image-based arterial input measured in the left ventricle of the heart. In the same animals, parametric maps of the [¹⁸F]-MPPF binding potential (BP_ND) were calculated from the entire 60-minute emission recordings using conventional reference tissue methods. All [¹⁸F]-MPPF recordings were followed by an [¹⁸F]-FDG emission recording, the summation of which was used for spatial normalization to a rat brain atlas. Test–retest variability of K₁-weighted uptake and BP_ND was 25%. TQD treatment evoked a global dose-dependent increase in K₁-weighted summation, which increased 2.5-fold with TQD (30 mg/kg), suggesting an IC₅₀ of 5 mg/kg TQD. All TQD doses increased the apparent [¹⁸F]-MPPF BP_ND calculated by the Logan method by 30%–40%, a bias likely arising due to increased free [¹⁸F]-MPPF concentrations in brain. TQD (15 mg/kg) evoked a 45% global increase in [¹⁸F]-FDG uptake, suggesting perturbation of brain energy metabolism due to P-gp blockade.     

Tracer Level Electrophilic Synthesis and Pharmacokinetics of the Hypoxia Tracer [18F]EF5

Purpose  

2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide labeled with [¹⁸F]-fluorine ([¹⁸F]EF5), a promising tracer for tumor hypoxia, has previously been synthesized in low yields and low specific radioactivity. In pharmacokinetic evaluations, in the presence of non-radioactive EF5, a uniform and low background uptake and high in vivo stability of [¹⁸F]EF5 have been demonstrated. Our purpose was to increase the specific radioactivity of [¹⁸F]EF5 to enable to study the pharmacokinetics at trace level.     

[18F]-FDG-PET/CT and [18F]-FAZA-PET/CT Hypoxia Imaging of Metastatic Thyroid Cancer: Association with Short-Term Progression After Radioiodine Therapy

Purpose

To examine the relationships between 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]-FDG) and hypoxia tracer [¹⁸F]fluoro-azomycinarabinofuranoside ([¹⁸F]-FAZA) and between ¹³¹I and [¹⁸F]-FAZA uptake in patients with metastatic thyroid cancer and to evaluate imaging features associated with short-term progression after ¹³¹I therapy.

Procedures

The study population was 20 patients (17 women and 3 men; mean age, 67 years) with metastatic thyroid cancer who underwent both [¹⁸F]-FDG- and [¹⁸F]-FAZA-positron emission tomography (PET)/X-ray computed tomography (CT) examinations before ¹³¹I therapy. Short-term response to radioiodine was assessed (mean follow-up, 19 months ±?9). PET parameters including [¹⁸F]-FDG-SUVmax, [¹⁸F]-FAZA-SUVmax, and [¹⁸F]-FAZA-tumor-to-muscle [T/M] were obtained. Mann-Whitney U, Wilcoxon signed-rank, or χ² tests were used to assess differences between two quantitative variables or compare categorical data. Predictive factors for short-term progression were investigated with logistic regression analysis.

Results

Eleven lymph node metastatic lesions were identified in 9 patients and 46 distant metastatic lesions (lung, 19; bone, 17; and liver, 10) in 14 patients. A total of 24 ¹³¹I-positive and 33 ¹³¹I-negative lesions were detected. SUVmax was significantly lower with [¹⁸F]-FAZA-PET/CT (1.3?±?0.6) than with [¹⁸F]-FDG-PET/CT (6.4?±?5.9, p?<?0.001). No significant correlation was observed between [¹⁸F]-FAZA-PET/CT and ¹³¹I imaging concerning visibility (p?=?0.36). After ¹³¹I therapy, 31 of 57 metastatic lesions displayed short-term progression. Multivariate logistic regression revealed that [¹⁸F]-FDG-SUVmax (p?=?0.022) and [¹⁸F]-FAZA-T/M (p?=?0.002) showed significant associations with short-term progression.

Conclusions

Although [¹⁸F]-FAZA uptake was low in metastatic thyroid cancers, not only glucose metabolism but also hypoxic conditions may be associated with progression after ¹³¹I therapy in patients with metastatic thyroid cancer.

     

Positron Emission Tomography Studies on Binding of Central Nervous System Drugs and P-Glycoprotein Function in the Rodent Brain

The permeability of the blood–brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT_1a receptor ligands, [¹⁸F]MPPF vs. [carbonyl-¹¹C]WAY100635. Under control conditions, the specific brain uptake of [¹⁸F]MPPF is five- to eightfold lower than that of [¹¹C]WAY100635. After cyclosporin A (CsA) modulation, [¹⁸F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-¹¹C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [¹⁸F]MPPF (two- to threefold). Brain uptake of the -adrenergic receptor ligands [¹¹C]carazolol and [¹⁸F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [¹⁸F]fluorocarazolol were doubled by CsA. Cerebral uptake of [¹¹C]carazolol in rats was much lower than that of [¹⁸F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [¹¹C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [¹¹C]verapamil and [¹¹C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [¹¹C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.     

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Background

Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo.

Methods

Using the Cu-mediated ¹⁸F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the ¹⁸F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [¹⁸F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461.

Results

[¹⁸F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 %?±?3 % and 3 %?±?1 % activity yields non-decay corrected). [¹⁸F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34?±?1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [¹⁸F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461.

Conclusion

Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

     

Whole-Body [18F]FDG-PET/MRI vs. [18F]FDG-PET/CT in Malignant Melanoma

Purpose

To assess the diagnostic performance of simultaneous whole-body 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared to [¹⁸F]FDG PET/x-ray computed tomography (CT) for detection of distant metastatic disease in patients with malignant melanoma.

Procedures

We included patients with malignant melanoma who underwent a single injection [¹⁸F]FDG dual-imaging protocol that included whole-body PET/CT and subsequent whole-body PET/MRI for staging or restaging purposes in a prospective setting. Images from both modalities were analyzed by two rater teams for the presence of metastatic lesions. PET/CT–PET/MRI overall agreement as well as region-based accuracies, sensitivities (Se), and specificities (Sp) were computed.

Results

Between July 2014 and December 2018, 22 patients were enrolled. Interrater agreement and overall accuracy (consensus reading) were 78.8 % (95 % CI 71–84.9) and 96.1 % (95 % CI 92.3–98) for PET/MRI and 78 % (70.2–84.3) and 97.4 % (95 % CI 93.7–98.9) for PET/CT, respectively (P?=?0.42). PET/MRI reached a region-based Se of 89.1 % (95 % CI 79.4–94.5) and a Sp of 100 %, whereas PET/CT showed a region-based Se of 92.7 % (95 % CI 84–96.9) and a Sp of 100 % for the detection of metastatic disease in malignant melanoma.

Conclusions

Whole-body [¹⁸F]FDG-PET/MRI appears to be comparable to [¹⁸F]FDG-PET/CT for lesion detection in patients with malignant melanoma.

     

[18F]-JK-PSMA-7 PET/CT Under Androgen Deprivation Therapy in Advanced Prostate Cancer

Purpose

PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [¹⁸F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [¹⁸F]-JK-PSMA-7 under ADT.

Procedures

We examined the performance of [¹⁸F]-JK-PSMA-7 in 70 patients (first cohort) with increasing or detectable PSA values under ADT (PSA < 2 ng/ml for 21/70 patients). We further analyzed 58 independent patients with PSA levels < 2 ng/ml under ADT, who were imaged with [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL (second cohort). Finally, we compared detection rates between [¹⁸F]-JK-PSMA-7, [⁶⁸Ga]PSMA-11, and [¹⁸F]DCFPyL.

Results

In the first cohort, we detected [¹⁸F]-JK-PSMA-7-positive lesions in 63/70 patients. In patients with PSA levels ≥ 2 ng/ml, the detection rate was 100 % (49/49). In patients with PSA < 2 ng/ml, the detection rate was significantly lower (66.7 %, 14/21, p = 9.7 × 10^?5) and dropped from 85.7 % (12/14, PSA levels between 0.3 and 2.0 ng/ml) to 28.6 % (2/7) for PSA levels < 0.3 ng/ml (p = 1.73 × 10^?2). In the second cohort (PSA < 2 ng/ml), the detection rate was 79.3 % (46/58) for [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL. Again, the detection rate was significantly higher (p = 1.1 × 10^?2) for patients with PSA levels between 0.3 and 2.0 ng/ml (87.0 %, 40/46) relative to those with PSA levels < 0.3 ng/ml (50 %, 6/12). No significant difference was found between [¹⁸F]-JK-PSMA-7 and [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL in patients with PSA levels < 2 ng/ml (p = 0.4295).

Conclusion

[¹⁸F]-JK-PSMA-7 PET showed a high detection rate in patients with PSA levels ≥ 0.3 ng/ml under ADT. The lower PSA threshold of 0.3 ng/ml for high detection rates was consistent across the three PSMA ligands. Thus, PSMA imaging is suitable for clinical follow-up of patients with increasing PSA levels under ADT.

     

An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ

Purpose

The aim of this study was to optimize the radiolabeling method of [¹⁸F]fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]FP-(+)-DTBZ) to fulfill the demand of preclinical and clinical application.

Procedures

Optimized labeling conditions were performed by altering the molar ratio of precursor to base (P/B), base species, solvents, reaction temperature, reaction time, and precursor concentration through manual radiosynthesis of [¹⁸F]FP-(+)-DTBZ. The conditions with the highest radiochemical yield (RCY) were applied to automated radiosynthesis, and the crude product was purified with a Sep-Pak Plus C18 cartridge. Quality control and stability of [¹⁸F]FP-(+)-DTBZ were carried out by HPLC. In vitro cellular uptake and blocking assays were conducted in human neuroblastoma cell line SH-SY5Y. In vivo imaging with small animal positron emission tomography (microPET) was performed with Sprague–Dawley rats.

Results

Under the optimized conditions (P/K₂CO₃?=?1:8, heating at 120 °C for 3 min in dimethyl sulfoxide), an RCY of 88.7 % was obtained with 1.0 mg precursor. The optimized reaction conditions were successfully applied to an automated module and gave a high activity yield (AY) of 30–55 % in about 40 min with a >?99.0 % radiochemical purity (RCP) and a >?44.4 GBq/μmol molar activity (A_m). Stability test displayed that the RCP retained >?98.0 % in 8 h in saline and in phosphate buffer saline (PBS, pH 7.4). In vitro cellular uptake assay showed accumulation of [¹⁸F]FP-(+)-DTBZ in SH-SY5Y cells, which could be significantly inhibited by vesicular monoamine transporter 2 (VMAT2) inhibitor DTBZ. MicroPET images of rat brain displayed that the striatum showed the highest uptake with a standardized uptake value (SUV) of 3.91?±?0.30 at ~?70 min. Co-injection with DTBZ (1.0 mg/kg) resulted in a 75 % decrease of the striatal SUV, confirming the specificity of [¹⁸F]FP-(+)-DTBZ to VMAT2.

Conclusions

We obtained an optimized radiolabeling method of [¹⁸F]FP-(+)-DTBZ and successfully applied it to a commercial available module. The automated synthesis gave a high AY and RCP of [¹⁸F]FP-(+)-DTBZ with high and specific binding to VMAT2, facilitating its routine application for VMAT2 tracing.

     

Preclinical Evaluation of a Novel TSPO PET Ligand 2-(7-Butyl-2-(4-(2-[18F]Fluoroethoxy)phenyl)-5-Methylpyrazolo[1,5-a]Pyrimidin-3-yl)-N,N-Diethylacetamide (18F-VUIIS1018A) to Image Glioma

Purpose

There is an urgent need for the development of novel positron emission tomography (PET) tracers for glioma imaging. In this study, we developed a novel PET probe ([¹⁸F]VUIIS1018A) by targeting translocator protein (TSPO), an imaging biomarker for glioma. The purpose of this preclinical study was to evaluate this novel TSPO probe for glioma imaging.

Procedures

In this study, we synthesized [¹⁹F]VUIIS1018A and the precursor for radiosynthesis of [¹⁸F]VUIIS1018A. TSPO binding affinity was confirmed using a radioligand competitive binding assay in C6 glioma cell lysate. Further, dynamic imaging studies were performed in rats using a microPET system. These studies include displacement and blocking studies for ligand reversibility and specificity evaluation, and compartment modeling of PET data for pharmacokinetic parameter measurement using metabolite-corrected arterial input functions and PMOD.

Results

Compared to previously reported TSPO tracers including [¹⁸F]VUIIS1008 and [¹⁸F]DPA-714, the novel tracer [¹⁸F]VUIIS1018A demonstrated higher binding affinity and BP_ND. Pretreatment with the cold analog [¹⁹F]VUIIS1018A could partially block tumor accumulation of this novel tracer. Further, compartment modeling of this novel tracer also exhibited a greater tumor-to-background ratio, a higher tumor binding potential and a lower brain binding potential when compared with other TSPO probes, such as [¹⁸F]DPA-714 and [¹⁸F]VUIIS1008.

Conclusions

These studies illustrate that [¹⁸F]VUIIS1018A can serve as a promising TSPO PET tracer for glioma imaging and potentially imaging of other solid tumors.

     

[18F]FLT PET for Non-Invasive Monitoring of Early Response to Gene Therapy in Experimental Gliomas

The purpose of this study was to investigate the potential of 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [¹⁸F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [¹⁸F]FLT accumulation within 3?days after initiation of therapy. The change in [¹⁸F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [¹⁸F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [¹⁸F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma.     

Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease

Purpose  We evaluated the usefulness of small animal brain positron emission tomography (PET) imaging with the amyloid-beta (Aβ) probe 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([¹⁸F]FDDNP) and with 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) for detection and quantification of pathological changes occurring in a transgenic mouse model of Alzheimer’s disease (Tg2576 mice). Procedures  [¹⁸F]FDDNP (n = 6) and FDG-PET scans (n = 3) were recorded in Tg2576 mice (age 13–15 months) and age-matched wild-type litter mates. Brain volumes of interest were defined by co-registration of PET images with a 3D MOBY digital mouse phantom. Regional [¹⁸F]FDDNP retention in mouse brain was quantified in terms of the relative distribution volume (DVR) using Logan’s graphical analysis with cerebellum as a reference region. Results  Except for a lower maximum brain uptake of radioactivity in transgenic animals, the regional brain kinetics as well as DVR values of [¹⁸F]FDDNP appeared to be similar in both groups of animals. Also for FDG, regional radioactivity retention was almost identical in the brains of transgenic and control animals. Conclusions  We could not detect regionally increased [¹⁸F]FDDNP binding and regionally decreased FDG binding in the brains of Tg2576 transgenic versus wild-type mice. However, small group differences in signal might have been masked by inter-animal variability. In addition, technical limitations of the applied method (partial volume effect, spatial resolution) for measurements in such small organs as mouse brain have to be taken into consideration.     

Comparison of [18F]-Tracers in Various Experimental Tumor Models by PET Imaging and Identification of an Early Response Biomarker for the Novel Microtubule Stabilizer Patupilone

Purpose  The suitability of [¹⁸F]FDG, [¹⁸F]FLT, [¹⁸F]FET, and [¹⁸F]FCH as non-invasive positron emission tomography (PET) biomarkers for monitoring response to chemotherapy was analyzed in various experimental tumor models. Procedures  Tracer uptake into three syngeneic rodent tumor models and ten human xenograft models was evaluated using semiquantitative analysis of small-animal PET data. Murine RIF-1 fibrosarcomas and [¹⁸F]FLT were selected to monitor the effects of the novel cytotoxic patupilone. Results  Except [¹⁸F]FCH, all tracers provided good tumor visualization. Highest [¹⁸F]FDG uptake was identified in syngeneic tumors. Xenograft models, however, showed low [¹⁸F]FDG SUVs and were better visualized by [¹⁸F]FLT. Monitoring the effects of patupilone on [¹⁸F]FLT uptake in RIF-1 tumors revealed a significant decrease of tracer uptake after 24 h, which strongly negatively correlated with apoptosis. Conclusion  [¹⁸F]FLT PET of experimental tumors is a viable complement to [¹⁸F]FDG for preclinical drug development. [¹⁸F]FLT may be an excellent biomarker for patupilone-induced apoptosis. T. Ebenhan and M. Honer contributed equally to this work. An erratum to this article can be found at