Value of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="SmallCaps">l</Emphasis>-tyrosine PET for the diagnosis of recurrent glioma

Purpose The prognosis of patients with recurrent gliomas depends on reliable and early diagnosis of tumour recurrence after initial therapy. In this context, magnetic resonance imaging (MRI) and computed tomography (CT) often fail to differentiate between radiation- and tumour-induced contrast enhancement. Furthermore, absence of contrast enhancement, or even of ¹⁸F-fluorodeoxyglucose uptake in PET, does not exclude recurrence. The aim of this study was to establish the diagnostic value of O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (FET) PET in recurrent gliomas.Methods Fifty-three patients with glioma (primary grading: 27=WHO grade IV, 16=grade III, 9=grade II, 1=grade I) and clinically suspected recurrence underwent FET PET scans 4–180 months after different treatment modalities. For semiquantitative evaluation, maximal SUV (SUV_max) and mean SUV within 80% and 70% isocontour thresholds (SUV₈₀/SUV₇₀) were evaluated and the respective ratios to the background (BG) were calculated. PET results were correlated with MRI/CT, clinical follow-up or biopsy findings.Results All patients presented with FET uptake, of varying intensity, in the area of the primary tumour after initial therapy. In the 42 patients with confirmed recurrence, there was additional distinct focal FET uptake with significantly higher values compared with those in the 11 patients without clinical signs of recurrence and showing only low and homogeneous FET uptake at the margins of the resection cavity. With respect to tumour grading, there was a slight but non-significant increase from WHO II (SUV_max/BG: 2.53±0.28) to WHO III (SUV_max/BG: 2.84±0.49) and WHO IV (SUV_max/BG: 3.55±1.07) recurrence.Conclusion FET PET reliably distinguishes between post-therapeutic benign lesions and tumour recurrence after initial treatment of low- and high-grade gliomas.     

Liver uptake of free fatty acids in vivo in humans as determined with 14(<Emphasis Type="Italic">R</Emphasis>,<Emphasis Type="Italic">S</Emphasis>)-[<Superscript>18</Superscript>F]fluoro-6-thia-heptadecanoic acid and PET

Increased delivery of circulating free fatty acids (FFA) to the liver has been implicated in the pathogenesis and progression of diabetes. The liver is inaccessible for direct measurement in humans in vivo. We measured liver FFA uptake with positron emission tomography (PET) and 14(R,S)-[¹⁸F]fluoro-6-thia-heptadecanoic acid ([¹⁸F]FTHA) in healthy men. We evaluated the use of graphical analysis and linear fit to describe uptake data over time, and compared the use of metabolite-corrected vs uncorrected input functions. Rapid accumulation of tracer in the liver was observed with time, leading to progressively higher tissue to blood radioactivity ratios. Using metabolite-corrected input function curves, linear fit to the data (r value) exceeded 0.99 in all subjects, during each fitting time frame. Values of liver FFA influx rate constant and uptake were 0.34±0.01 ml min^–1 ml^–1 and 0.20±0.02 µmol min^–1 ml^–1, respectively, and were minimally affected by the choice of the fitting interval. Expressed per unit mass, liver FFA uptake was ~50 times higher than that reported in skeletal muscle; in the whole organ, FFA uptake was twice as high as in skeletal muscles. The use of metabolite-uncorrected input functions significantly worsened the spread of data around the fitted line and led to a remarkable underestimation of liver FFA uptake at all time intervals. In conclusion, our data provide non-invasive quantification of hepatic FFA uptake in humans, showing the liver to handle a high FFA flux. [¹⁸F]FTHA-PET appears a valuable tool for the investigation of hepatic FFA turnover in humans.     

Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (<Emphasis Type="Italic">S</Emphasis>,<Emphasis Type="Italic">S</Emphasis>)-[<Superscript>18</Superscript>F]FMeNER-D<Subscript>2</Subscript>: a human whole-body PET study

Purpose (S,S)-[¹⁸F]FMeNER-D₂ is a recently developed positron-emission tomography (PET) radioligand for in vivo quantification of the norepinephrine transporter system. The aim of this study was to provide dosimetry estimates for (S,S)-[¹⁸F]FMeNER-D₂ based on human whole-body PET measurements. Methods PET scans were performed for a total of 6.4 h after the injection of 168.9 ± 31.5 MBq of (S,S)-[¹⁸F]FMeNER-D₂ in four healthy male subjects. Volumes of interest were drawn on the coronal images. Estimates of the absorbed dose of radiation were calculated using the OLINDA software. Results Uptake was largest in lungs, followed by liver, bladder, brain and other organs. Peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lung (21.6%ID at 0.3 h), liver (5.1%ID at 0.3 h), bladder (12.2%ID at 6 h) and brain (2.3%ID at 0.3 h). The largest absorbed dose was found in the urinary bladder wall (0.039 mGy/MBq). The calculated effective dose was 0.017 mSv/MBq. Conclusion Based on the distribution and dose estimates, the estimated radiation burden of (S,S)-[¹⁸F]FMeNER-D₂ is lower than that of [¹⁸F]FDG. The radioligand would allow multiple PET examinations in the same research subject per year.     

The potential use of 2-[<Superscript>18</Superscript>F]fluoro-2-deoxy-<Emphasis Type="SmallCaps">D</Emphasis>-galactose as a PET/CT tracer for detection of hepatocellular carcinoma

Purpose  

The aim of the study was to evaluate the feasibility of using the hepatocyte-specific positron emission tomography (PET) tracer 2-[¹⁸F]fluoro-2-deoxy-D-galactose (FDGal) as a tracer for hepatocellular carcinoma (HCC).     

Diagnostic impact of PET with <Superscript>18</Superscript>F-FDG, <Superscript>18</Superscript>F-DOPA and 3-<Emphasis Type="Italic">O</Emphasis>-methyl-6-[<Superscript>18</Superscript>F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma

Purpose In patients with medullary thyroid carcinoma (MTC), rising levels of the tumour markers calcitonin and CEA after primary surgery indicate tumour recurrence or metastases. The only chance of cure is the resection of localised tumour tissue. For positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and ¹⁸F-dihydroxyphenylalanine (¹⁸F-DOPA), sensitivities of 78% and 63% have been reported, but in a considerable percentage of MTC patients the source of tumour marker elevation is not detected. The aim of this retrospective data evaluation was to compare the value of PET with ¹⁸F-FDG, ¹⁸F-DOPA and the amino acid tracer 3-O-methyl-6-[¹⁸F]fluoro-DOPA (¹⁸F-OMFD) in the detection of MTC recurrence. Methods Fifteen patients with elevated calcitonin were investigated with PET as part of their individual clinical work-up. All patients underwent ¹⁸F-FDG PET and ¹⁸F-DOPA PET, and ten patients underwent ¹⁸F-OMFD PET. Results With ¹⁸F-FDG, seven patients showed foci in the neck, mediastinum, upper abdomen or bone. In seven patients, ¹⁸F-DOPA revealed suspicious foci; five of these seven patients showed partially corresponding uptake of ¹⁸F-FDG in the neck and mediastinum. Two of these patients underwent surgery and metastases were verified. With ¹⁸F-OMFD, a small focus in the liver was suspected in one patient without a correlate on ¹⁸F-FDG PET, ¹⁸F-DOPA PET or conventional imaging. Conclusion ¹⁸F-FDG and ¹⁸F-DOPA showed foci that were highly suspicious for local recurrence or metastasis of MTC, although histological verification in these patients with numerous previous surgical interventions was performed in only two patients. The amino acid tracer ¹⁸F-OMFD had no diagnostic impact in these patients.     

Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)-<Emphasis Type="Italic">N</Emphasis>-(3,3,3-[<Superscript>18</Superscript>F]trifluoropropyl)acetamide, [<Superscript>18</Superscript>F]EF3

The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic cells. Radiosynthesis of [¹⁸F]EF3 was recently performed by our group. Our aim was to study the pharmacokinetics, biodistribution, metabolism and specificity for hypoxia of [¹⁸F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour-bearing C3H mice were injected intravenously with [¹⁸F]EF3 and allowed to breathe air, 10% O₂ or carbogen until sacrifice 5–770 min after injection. Radioactivity was measured ex vivo in various organs, including urine and faeces. Selected organs were additionally processed to measure tracer metabolites with high-performance liquid chromatography. The half-life in blood was 73.9 min. [¹⁸F]EF3 was eliminated mainly via the kidneys, with 75% of the injected activity found in the urine by 12 h 50 min. The biodistribution was fast and homogeneous except in the brain and the bone, where it was significantly lower, and in the liver and the kidney, where it was significantly higher. In most organs, the exceptions being the gastrointestinal and urinary tract, tissue-to-blood ratios were below or close to unity. In tumours, a relative accumulation of the tracer was observed with time, which, at 220 min after injection, depended on tumour strain and oxygenation conditions, i.e. 10% O₂ significantly increased the tumour-to-muscle ratio whereas carbogen decreased it. [¹⁸F]EF3 was rapidly metabolised in the kidney and the liver. [¹⁸F]EF3 is a promising tracer for detection of tumour hypoxia. A phase I study in head and neck cancer patients is in progress at our institution.     

Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (<Emphasis Type="Italic">S</Emphasis>,<Emphasis Type="Italic">S</Emphasis>)-[<Superscript>18</Superscript>F]FMeNER-D<Subscript>2</Subscript>

Purpose  In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. Methods  Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[¹⁸F]FMeNER-D₂ under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP_ND obtained with the simplified reference tissue model. Results  NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml. Conclusion  The results indicate that clinical doses of atomoxetine would occupy NET almost completely.     

Synthesis and evaluation of a new vesamicol analog <Emphasis Type="Italic">o</Emphasis>-[<Superscript>11</Superscript>C]methyl-<Emphasis Type="Italic">trans</Emphasis>-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter

Introduction

We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer’s diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [¹¹C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.

Method

[¹¹C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [¹¹C]methyl iodide, with a radiochemical yield of 60–75 %, a radiochemical purity of greater than 98 %, and a specific activity of 5–10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [¹¹C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET–CT imaging study were performed to check the binding selectivity of [¹¹C]OMDV for VAChT.

Results

In vivo studies demonstrated [¹¹C]OMDV passage through the blood–brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [¹¹C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [¹¹C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET–CT imaging revealed inhibition of [¹¹C]OMDV accumulation in the brain by co-administration of vesamicol.

Conclusion

[¹¹C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [¹¹C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.

     

Diagnosis of tumor in the nasal cavity and paranasal sinuses with [<Superscript>11</Superscript>C]choline PET: Comparative study with 2-[<Superscript>18</Superscript>F]fluoro-2-deoxy-<Emphasis Type="SmallCaps">d</Emphasis>-glucose (FDG) PET

[11C]choline (11C-choline) positron emission tomography (PET) was performed to evaluate its clinical utility in the diagnosis of tumors in the nasal cavity and paranasal sinuses. We studied 22 patients with suspicion of malignant tumors in the nasal cavity and paranasal sinuses. Tumor uptake of 11C-choline was measured with standardized uptake value (SUV) and correlated with the pathological diagnosis. 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET was performed in all patients for comparison. Both 11C-choline and FDG PET depicted squamous cell carcinoma showing an increased activity significantly higher than that of normal tissue, and these SUVs were significantly higher than those of benign lesions. FDG uptake in malignant tumors as a whole was variable. Although 11C-choline uptake in squamous cell carcinoma was lower than FDG uptake, 11C-choline uptake in malignant tumors was relatively uniform and statistical significance was found. PET with 11C-choline may be useful to diagnosis tumors in the nasal cavity and paranasal sinuses.     

Evaluation of [<Superscript>18</Superscript>F]-choline PET/CT for staging and restaging of prostate cancer

Purpose To evaluate the accuracy of [¹⁸F]-choline (FCH) positron emission tomography/computed tomography (PET/CT) for staging and restaging of prostate cancer. Methods FCH PET/CT was performed in 111 patients with prostate cancer using 200 MBq FCH: 43 patients [mean age 63 years; mean prostrate specific antigen (PSA) 11.58 μg/l] were examined for initial staging, and 68 patients (mean age 66.4 years) were examined for restaging (mean PSA 10.81 μg/l). FCH PET/CT results were correlated to histopathology, bone scan, morphology as revealed by magnetic resonance imaging (MRI) and CT, PET/CT follow-up and PSA follow-up after therapy. Results FCH PET/CT scans at initial staging correctly showed no metastases in 36/38 patients undergoing radical surgery, as confirmed by PSA levels <0.1 μg/l 6 months postoperatively. Lymphadenectomy was performed in 24 of these patients, revealing four false FCH-negative lymph nodes (LN). In one patient, only lymphadenectomy was performed since a FCH-positive LN was confirmed by histology. Four patients showed FCH-positive bone metastases, as proven by bone scan. FCH PET/CT scans at restaging correctly revealed local recurrence in 36 patients. No pathological FCH uptake was observed in 11 patients with biochemical recurrence. Twenty-three patients showed FCH-positive LN. Twenty LN were surgically removed in seven patients. Histopathology verified metastases in all LN, but revealed two additional metastastic, FCH-negative LN. Seventeen patients showed FCH-positive bone metastases, as proven by bone scan or MRI. Sensitivity to detect recurrent disease was 86%. Conclusion The results obtained using FCH PET/CT scans for initial N-staging were discouraging, especially in terms of its inability to detect small metastases. Recurrent disease can be localized reliably in patients with PSA levels of >2 μg/l.     

Reliable radiosynthesis of 4-[<Superscript>10</Superscript>B]borono-2-[<Superscript>18</Superscript>F]fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-phenylalanine with quality assurance for boron neutron capture therapy-oriented diagnosis

Objective

The aim of this study was to establish a reliable and routine method for the preparation of 4-[¹⁰B]borono-2-[¹⁸F]fluoro-l-phenylalanine (l-[¹⁸F]FBPA) for boron neutron capture therapy-oriented diagnosis using positron emission tomography.

Methods

To produce l-[¹⁸F]FBPA by electrophilic fluorination of 4-[¹⁰B]borono-l-phenylalanine (l-BPA) with [¹⁸F]acetylhypofluorite ([¹⁸F]AcOF) via [¹⁸F]F₂ derived from the ²⁰Ne(d,α)¹⁸F nuclear reaction, several preparation parameters and characteristics of l-[¹⁸F]FBPA were investigated, including: pre-irradiation for [¹⁸F]F₂ production, the carrier F₂ content in the Ne target, l-BPA-to-F₂ ratios, separation with high-performance liquid chromatography (HPLC) using 10 different eluents, enantiomeric purity, and residual trifluoroacetic acid used as the reaction solvent by gas chromatography-mass spectrometry.

Results

The activity yields and molar activities of l-[¹⁸F]FBPA (n?=?38) were 1200?±?160 MBq and 46–113 GBq/mmol, respectively, after deuteron-irradiation for 2 h. Two 5 min pre-irradiations prior to [¹⁸F]F₂ production for ¹⁸F-labeling were preferable. For l-[¹⁸F]FBPA synthesis, 0.15–0.2% of carrier F₂ in Ne and l-BPA-to-F₂ ratios?>?2 were preferable. HPLC separations with five of the 10 eluents provided injectable l-[¹⁸F]FBPA without any further formulation processing, which resulted in a synthesis time of 32 min. Among the five eluents, 1 mM phosphate-buffered saline was the eluent of choice. The l-[¹⁸F]FBPA injection was sterile and pyrogen-free, and contained very small amounts of D-enantiomer (<?0.1% of l-[¹⁸F]FBPA), l-BPA (<?1% of l-FBPA), and trifluoroacetic acid (<?0.5 ppm).

Conclusions

l-[¹⁸F]FBPA injection was reliably prepared by the electrophilic fluorination of l-BPA with [¹⁸F]AcOF followed by HPLC separation with 1 mM phosphate-buffered saline.

     

Potential impact of [<Superscript>18</Superscript>F]3'-deoxy-3'-fluorothymidine versus [<Superscript>18</Superscript>F]fluoro-2-deoxy-<Emphasis Type="SmallCaps">d</Emphasis>-glucose in positron emission tomography for colorectal cancer

Ohne Zusammenfassung     

Prognostic implications of <Superscript>62</Superscript>Cu-diacetyl-bis (<Emphasis Type="Italic">N</Emphasis><Superscript>4</Superscript>-methylthiosemicarbazone) PET/CT in patients with glioma

Objective

The potential of positron emission tomography/computed tomography using ⁶²Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of ⁶²Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG).

Method

56 patients with glioma of World Health Organization grade 2–4 were enrolled. All participants had undergone both ⁶²Cu-ATSM PET/CT and ¹⁸F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox’s proportional hazards model.

Results

Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using ⁶²Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using ⁶²Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p?<?0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using ⁶²Cu-ATSM PET/CT showed significant difference of progression-free survival (p?<?0.05).

Conclusions

⁶²Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to ¹⁸F-FDG PET/CT.

     

Quantification of (<Emphasis Type="Italic">R</Emphasis>)-[<Superscript>11</Superscript>C]PK11195 binding in rheumatoid arthritis

Purpose  Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[¹¹C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[¹¹C]PK11195 binding in the knee joints of RA patients. Methods  Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[¹¹C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[¹¹C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V_d) and standardized uptake values (SUV) were evaluated. Results  AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V_d obtained using different input functions (R ²=0.80–1.00) and between V_d obtained with one- and two-tissue reversible compartment models (R ²=0.75–0.94). A high correlation was observed between optimal V_d and SUV after injection (R ²=0.73). Conclusion  (R)-[¹¹C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V_d, SUV is a practical alternative for clinical use. Financial support: There were no sources of financial support other than the VU University Medical Centre. The authors had full control of all primary data and agree to allow EJNM to review their data if requested.     

Uptake of 4-borono-2-[<Superscript>18</Superscript>F]fluoro-<Emphasis Type="SmallCaps">L</Emphasis>-phenylalanine in sporadic and neurofibromatosis 2-related schwannoma and meningioma studied with PET

Purpose Meningiomas and schwannomas associated with neurofibromatosis 2 (NF2) are difficult to control by microsurgery and stereotactic radiotherapy alone. Boron neutron capture therapy (BNCT) is a chemically targeted form of radiotherapy requiring increased concentration of boron-10 in tumour tissue. PET with the boron carrier 4-borono-2-[¹⁸F]fluoro-L-phenylalanine ([¹⁸F]FBPA) allows investigation of whether 4-borono-L-phenylalanine (BPA) concentrates in NF2 tumours, which would make BNCT feasible. Methods We studied dynamic uptake of [¹⁸F]FBPA in intracranial meningiomas (n=4) and schwannomas (n=6) of five sporadic and five NF2 patients. Tracer input function and cerebral blood volume were measured. [¹⁸F]FBPA uptake in tumour and brain was assessed with a three-compartmental model and graphical analysis. These, together with standardised uptake values (SUVs), were used to define tumour-to-brain [¹⁸F]FBPA tissue activity gradients. Results Model fits with three parameters K ₁ (transport), k ₂ (reverse transport) and k ₃ (intracellular metabolism) were found to best illustrate [¹⁸F]FBPA uptake kinetics. Maximum SUV was two- to fourfold higher in tumour as compared with normal brain and independent of NF2 status. The increased uptake was due to higher transport of [¹⁸F]FBPA in tumour. In multiple-time graphical analysis (MTGA, Gjedde-Patlak plot) the tumour-to-brain [¹⁸F]FBPA influx constant (K _i -MTGA) ratios varied between 1.8 and 5.4 in NF2-associated tumours while in sporadic tumours the ratio was 1–1.4. Conclusion [¹⁸F]FBPA PET offers a viable means to evaluate BPA uptake in meningiomas and schwannomas in NF2. Based on our results on tumour uptake of [¹⁸F]FBPA, some of these benign neoplasms may be amenable to BNCT. Financial support: This work was sponsored in part by the Department of Army, Grant No. DAMD17-00-1-0545. The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, USA, is the awarding and administering acquisition office. The content of the information of this paper does not necessarily reflect the position or the policy of the US Government.     

Imaging the norepinephrine transporter with positron emission tomography: initial human studies with (<Emphasis Type="Italic">S,S</Emphasis>)-[<Superscript>18</Superscript>F]FMeNER-D<Subscript>2</Subscript>

Introduction (S,S)-[¹⁸F]FMeNER-D₂ is a recently developed positron emission tomography (PET) ligand for in vivo quantification of norepinephrine transporter. A monkey occupancy study with the radioligand indicated that (S,S)-[¹⁸F]FMeNER-D₂ can be useful for quantitative PET analysis. In this preliminary study, regional distributions in the living human brain were evaluated. Materials and methods Brain PET measurements were performed for a total of 255 min after the injection of 188.3 ± 5.7 MBq of (S,S)-[¹⁸F]FMeNER-D₂ in four healthy male subjects. Regions of interests were drawn on the thalamus and the caudate in the coregistered MRI/PET images. Results (S,S)-[¹⁸F]FMeNER-D₂ displayed good brain penetration and selective retention in regions rich in norepinephrine reuptake sites. The transient peak equilibrium was reached during the PET measurements. The ratios of radioactivity uptake in the thalamus to that in the caudate were 1.50 ± 0.06 for the time period of 90–255 min. Conclusion The present preliminary investigation indicates that (S,S)-[¹⁸F]FMeNER-D₂ has suitable characteristics for probing the norepinephrine reuptake system with PET in the human brain.     

Comparison of [<Superscript>18</Superscript>F]FHBG and [<Superscript>14</Superscript>C]FIAU for imaging of <Emphasis Type="Italic">HSV1-tk</Emphasis> reporter gene expression: adenoviral infection vs stable transfection

Earlier studies involving comparison of different reporter probes have shown conflicting results between pyrimidine nucleosides [e.g., 2'-fluoro-2'-deoxy-1--d-arabinofuranosyl-5-iodouracil (FIAU)] and acycloguanosine derivatives [e.g., penciclovir (PCV), 9-(4-fluoro-3-hydroxymethylbutyl)guanine (FHBG)]. We hypothesized that this reported discrepancy may be related to how the reporter gene is delivered to the cells—stably transfected vs adenoviral infection. We directly compared the uptake characteristics of [¹⁸F]FHBG, [³H]PCV, and [¹⁴C]FIAU in cell culture and in vivo using an adenoviral mediated gene transfer model and stably transfected cells. We further compared the uptake of three reporter probes using both HSV1-tk and a mutant HSV1-sr39tk expressing cells to assess the optimal reporter probe/reporter gene combination. [¹⁴C]FIAU accumulation was greater than that of [³H]PCV and [¹⁸F]FHBG in control cells and in HSV1-tk stably transfected cells (P<0.001). After infection of C6 cells with AdCMV-HSV1-tk (1.5×10⁸ pfu), [¹⁸F]FHBG and [³H]PCV accumulation was significantly greater than that of [¹⁴C]FIAU (P<0.01). [¹⁸F]FHBG and [³H]PCV accumulated to a significantly greater extent than [¹⁴C]FIAU in C6-stb-sr39tk+ and AdCMV-HSV1-sr39tk infected C6 cells (P<0.001). Results from the nude mice supported the results in cell culture. [¹⁴C]FIAU led to significantly higher %ID/g in C6-stb-tk+ xenografts than [¹⁸F]FHBG (P<0.05); however, compared with [¹⁴C]FIAU, [¹⁸F]FHBG led to as high %ID/g in HSV1-tk expressing hepatocytes and to significantly greater %ID/g in C6-stb-sr39tk+ xenografts and HSV1-sr39tk expressing hepatocytes. Dynamic sequential images showed that [¹⁸F]FHBG was well retained in HSV1-sr39tk expressing cells (C6-stb-sr39tk+) for at least 4 h after injection, while it was rapidly cleared from HSV1-tk expressing cells (MH3924A-stb-tk+). [¹⁴C]FIAU accumulated in HSV1-tk stably expressing cells to a greater extent than either [³H]PCV or [¹⁸F]FHBG. However, the accumulation of [³H]PCV and [¹⁸F]FHBG in adenoviral infected C6 cells or hepatocytes was equivalent to or greater than that of [¹⁴C]FIAU. These results may be due to intracellular biochemical changes (e.g., thymidine) when cells are infected with adenovirus. For adenoviral studies, the [¹⁸F]FHBG/HSV1-sr39tk combination was shown to be more sensitive than the [¹⁴C]FIAU/HSV1-tk combination HSV1-tk.     

<Superscript>18</Superscript>F-Fluoroglucosylation of peptides,exemplified on <Emphasis Type="Italic">cyclo</Emphasis>(RGDfK)

Purpose  Oxime formation between an aminooxy-functionalized peptide and an ¹⁸F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides. Materials and methods  Here, the potential of using routinely produced and thus readily available [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide. Results  The use of [¹⁸F]FDG from routine production ([¹⁸F]FDGTUM) containing an excess of d-glucose did not allow the radiosynthesis of [¹⁸F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [¹⁸F]FDG for the routine clinical synthesis of ¹⁸F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [¹⁸F]FDG obtained via HPLC separation of [¹⁸F]FDGTUM from excess glucose, however, afforded [¹⁸F]FDG-RGD in yields of 56–93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120°C and pH 2.5, and a peptide concentration of 5 mM. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [¹⁸F]FDG-RGD showed increased tumour accumulation compared to the “gold standard” [¹⁸F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds. Conclusion  These data demonstrate that chemoselective ¹⁸F-labelling of aminooxy-functionalized peptides using n.c.a. [¹⁸F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of ¹⁸F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [¹⁸F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [¹⁸F]FDG-synthesis, [¹⁸F]fluoroglucosylation of peptides may represent a promising alternative to currently used chemoselective one-step ¹⁸F-labelling protocols.