Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates

Purpose

There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-d-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[¹¹C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([¹¹C]HACH242). This paper reports the evaluation of [¹¹C]HACH242 PET in non-human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil.

Procedures

Eight 90-min dynamic [¹¹C]HACH242 PET scans were acquired in three male anaesthetised rhesus monkeys, including a retest session of subject 1, at baseline and 10 min after intravenous 10 mg/kg radiprodil. Standardised uptake values (SUV) were calculated for 9 brain regions. Arterial blood samples were taken at six timepoints to characterise pharmacokinetics in blood and plasma. Reliable input functions for kinetic modelling could not be generated due to variability in the whole-blood radioactivity measurements.

Results

[¹¹C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (±?standard deviation, SD) T_max was 17?±?7 min in baseline scans and 24?±?15 min in radiprodil scans. The rate of radioligand metabolism in plasma (primarily to polar metabolites) was high, with mean parent fractions of 26?±?10 % at 20 min and 8?±?5 % at 85 min. Radiprodil increased [¹¹C]HACH242 whole-brain SUV in the last PET frame by 25 %, 1 %, 3 and 17 % for subjects 1, 2, 3 and retest of subject 1, respectively. The mean brain to plasma ratio was 5.4?±?2.6, and increased by 39 to 110 % in the radiprodil condition, partly due to lower parent plasma radioactivity of ?11 to ?56 %.

Conclusions

The present results show that [¹¹C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [¹¹C]HACH242 brain uptake. These findings may be explained by variations in cerebral blood flow, a low fraction of specifically bound tracer, or interactions with endogenous NMDA receptor ligands at the binding site. Further experiments of ligand interactions are necessary to facilitate the development of radiotracers for in vivo imaging of the ionotropic NMDA receptor.

     

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.     

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.     

Potential of Dual Time Point FDG-PET Imaging in Differentiating Malignant from Benign Pleural Disease

Aim  The aim of this study was to assess the utility of dual time point ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) imaging in differentiating benign from malignant pleural disease. Methods  Fifty-five consecutive patients of suspected malignant pleural mesothelioma (MPM) and recurrence of MPM who were referred for the evaluation underwent two sequential ¹⁸F-FDG-PET scans (dual time point imaging). The average percent change in the maximum standardized uptake values (Δ%SUVmax) of the lesion/lesions between time point 1 (SUV_max1) and time point 2 (SUV_max2) was calculated. All PET results were correlated with the histopathological or cytopathology results. Patients were divided into three principal groups (A = newly diagnosed MPM, B = recurrent MPM, and C = benign pleural disease). The parameters of ¹⁸F-FDG uptake (SUV_max values and its changes over time) were compared among groups. Results  Among the 55 patients who had undergone dual time point ¹⁸F-FDG-PET studies, 44 were diagnosed with MPM (28 newly diagnosed and 16 had recurrence). The PET studies demonstrated 229 malignant pleural lesions in these patients. The remaining 11 patients were proven to have benign pleural disease. The mean ± SD of the SUV_max1, SUV_max2, and the Δ%SUV_max of the all lesions of each patient in groups A, B, and C were 5.0 ± 2.2%, 5.8 ± 2.8%, and 12.8 ± 8.4%; 4.6 ± 1.7%, 5.3 ± 2.0%, 13.8 ± 9.2%; and 1.6 ± 0.4%, 1.4 ± 0.3%, and–9.6 ± 19.1%, respectively. The mean ± SD of the SUV_max1, SUV_max2, and Δ%SUV_max in patients with both newly diagnosed and recurrent MPM were significantly higher than those of benign pleural disease group (p < 0.0001). For each patient, the most intense (hottest) lesion’s SUV_max1, SUV_max2, and Δ%SUV_max were also compared among the aforementioned groups, and these results again confirmed that MPM lesions had significantly higher values than those of benign pleural lesions (p < 0.0001). Conclusions  There is an increasing uptake of ¹⁸F-FDG over time in pleural malignancies, whereas the uptake in benign pleural disease generally stays stable or decreases over time. Therefore, dual time point imaging appears to be an effective approach in differentiating benign from malignant pleural disease, which increases the sensitivity and is also helpful in guiding the biopsy site for a successful diagnosis.     

Time Sensitivity: A Parameter Reflecting Tumor Metabolic Kinetics by Variable Dual-Time F-18 FDG PET Imaging

Objectives  The aim of this study was to define and investigate the time sensitivity of tumors by variable dual-time fluorodeoxyglucose positron emission tomography (FDG PET). Methods  Variable dual-time (t) protocol (P) FDG PET–computed tomography (CT) scans from 40 patients with pathologically proven head and neck tumors without brain metastasis were analyzed. The first protocol (P.I) consisted of 26 patients with early (E) and delayed (D) PET–CT obtained at 106 ± 15 and 135 ± 16 min after injection of 16.3 ± 1.9 mCi FDG. The second protocol (P.II) recruited 14 patients with E- and D-PET performed at 54 ± 13 and 151 ± 28 min after injection of 9.6 ± 1.7 mCi FDG. The maximum standardized uptake values (SUVs) were measured in the primary tumor (CA1) and the cerebellum (CBL). The time sensitivity (S) was defined as d{ln(SUV)}/d{ln(t)} and its value was obtained by linear regression of ln(D-SUV/E-SUV) vs ln(t _D/t _E). Patients with cerebellar variations greater than 30% in SUV between E- and D-PET was excluded from the analysis. Results  Two patients from P.I were excluded due to wide cerebellar SUV variations. D-SUV were significantly higher than E-SUV in CA1 for both P.I (18.9 ± 6.9 vs 14.8 ± 5.6, p < 0.0005) and P.II (11.5 ± 7.9 vs 9.7 ± 6.9, p = 0.013). The S values for CA1 in P.I and P.II were 0.67 and 0.17, respectively. The D-SUV were also higher than E-SUV in CBL for both P.I (12.5 ± 1.6 vs 11.6 ± 1.6, p < 0.0005) and P.II (7.6 ± 1.6 vs 7.0 ± 1.6, p = 0.008). The S values for CBL in P.I and P.II were 0.47 and 0.04, respectively, which were over 1.4-fold smaller than that of CA1, suggesting fundamental kinetic differences between CA1 and CBL. Conclusions  The time sensitivity factor reflects another kinetic parameter of tumor metabolism besides SUV when using variable dual-time FDG PET. It offers another useful diagnostic tool in optimizing choices of dual-time protocols for oncologic PET–CT and in reducing SUV variations due to time interval differences with corrections using S.     

11C-Methionine-PET for Evaluation of Carbon Ion Radiotherapy in Patients with Pelvic Recurrence of Rectal Cancer

Purpose  Progress of the novel carbon ion radiotherapy (CIRT) in the treatment of cancers has created the need for a method to accurately evaluate the response. We investigated whether l-[¹¹C]methyl-methionine (¹¹C-methionine) uptake at pre- and post-CIRT could be an early response predictor in patients with pelvic recurrence of rectal cancer. Procedures   ¹¹C-Methionine-positron emission tomography (PET) was performed prospectively in 53 patients with pelvic recurrence of rectal cancer before CIRT, and 48 patients were performed ¹¹C-methionine PET at 1 month after CIRT. ¹¹C-Methionine tumor uptake was measured by the tumor to muscle ratio (T/M ratio). The T/M ratios were evaluated in relation to clinical outcomes such as local re-recurrence, distant metastasis, and survival. The response to CIRT was also judged by computed tomography (CT) and magnetic resonance imaging (MRI). ¹¹C-Methionine PET judgment was compared with CT/MRI judgment regarding the relevance to clinical outcome. Results  Baseline T/M ratio was 5.27 ± 1.90 (mean ± SD) in patients without developing local re-recurrence and 7.66 ± 3.17 in patients with local re-recurrence (p = 0.023, Mann–Whitney U test). Post-CIRT T/M ratios were 3.10 ± 1.28 in patients without local re-recurrence and 6.15 ± 2.98 in patients with local re-recurrence (p = 0.006, Mann–Whitney U test). By Kaplan–Meier analysis with log-rank test, patients with a baseline T/M ratio of ≦7.6 or a post-CIRT T/M ratio of ≦5.0 had significant lower pelvic re-recurrence rate. However, the percent change (reduction rate) from baseline to post-CIRT T/M ratio did not have significant relation to pelvic re-recurrence. There were no significant differences between ¹¹C-methionine results (baseline T/M ratio, post-CIRT T/M ratio and percent change) and other clinical parameters (distant metastasis and survival). Conclusion   ¹¹C-methionine-PET can be used for early prediction of local re-recurrence after CIRT. Because CIRT is local therapy, ¹¹C-methionine-PET cannot predict distant metastasis or survival after CIRT.     

Analysis of (R)- and (S)-[11C]rolipram Kinetics in Canine Myocardium for the Evaluation of Phosphodiesterase-4 with PET

Purpose  

(R)-[¹¹C]rolipram and (S)-[¹¹C]rolipram have been proposed to investigate phosphodiesterase-4 and, indirectly, cAMP-mediated signaling with PET. This study assessed binding of these tracers to phosphodiesterase-4 in canine myocardium.     

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

Purpose

The glutamine analogue (2S, 4R)-4-[¹⁸F]fluoroglutamine ([¹⁸F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice.

Procedures

[¹⁸F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance liquid chromatography. An orthotopic model was created by injecting luciferase-expressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1^nu mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1^nu/nu mice. Dynamic PET images were acquired after injecting 10–12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1^nu/nu and 6 C57BL/6J mice was performed after 9–14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood radioactivity and apply the data to multiple pharmacokinetic models.

Results

Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n?=?12) a tumor-to-muscle (flank) ratio of 1.9?±?0.7 (range 1.3–3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake.

Conclusions

The results reinforce that [¹⁸F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.

     

Acute lymphoblastic leukemia and obesity: increased energy intake or decreased physical activity?

Background  Obesity is a well-known problem in children with acute lymphoblastic leukemia (ALL), and it might be the result of an excess in energy intake, reduced energy expenditure, or both. The aim of this study is to describe energy intake and physical activity during treatment for ALL with intermittent dexamethasone (DEXA). Methods  Body mass index (BMI), energy intake, and physical activity were measured in 16 ALL patients on maintenance treatment and in 17 healthy controls. ALL patients were measured during (“on DEXA”) and in between (“off DEXA”) DEXA treatments. Results  In patients, the mean increase in BMI z-score was 1.4 ± 1.1. Energy intake on DEXA was higher (2,125.9 ± 476.0 vs 1,775.1 ± 426.1 kcal/24 h, p < 0.05) and energy intake off DEXA was lower (1,305.0 ± 249.4 vs 1,775.1 ± 426.1 kcal/24 h, p < 0.05), compared to healthy controls. Physical activity on DEXA was lower compared to healthy controls (30.0 ± 3.9 vs 40.0 ± 6.0 kcal kg⁻¹ 24 h⁻¹, p < 0.001 and 7,303.1 ± 4,622.9 vs 13,927.2 ± 3,822.7 steps, p < 0.05). Physical activity off DEXA was not different compared to healthy controls. Conclusion  Weight gain in patients on ALL treatment might be owing to increased energy intake and decreased physical activity during treatment with DEXA.     

Investigating the Existence of Quantum Metabolic Values in Non-Hodgkin’s Lymphoma by 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography

Objectives To investigate the existence of quantum metabolic values in various subtypes of non-Hodgkin’s lymphoma (NHL). Methods Fifty-eight patients with newly diagnosed NHL and positron emission tomography (PET) performed within three months of biopsy were included. The standardized uptake value (SUV) from PET over the area of biopsy and serum glucose [Glc] were recorded. The group glucose sensitivity(G) for indolent and aggressive NHL was obtained by linear regression with ln(SUV) = G·ln[Glc] + C, where C is a constant for the group. Finally, the individual’s glucose sensitivity (g) was obtained by g = {ln(SUV)-C}/ln[Glc], along with their means in various subtypes of NHL. To further investigate the influence of extreme [Glc] conditions, the SUVs corrected by the individually calculated g at various glucose levels, [Glc′] using SUV′ =SUV·{[Glc′]/[Glc]} ^g , were compared to the original SUVs for both indolent and aggressive NHL. Results The averaged g (=G) for aggressive was significant different from that for indolent NHL (−0.94 ± 0.51 vs. +0.13 ± 0.10, respectively, p < 0.00005). There were significant differences in SUV for [Glc] < 80 or >110 mg/dl for both types of NHL. Unlike overlap among SUVs between NHL subtypes, the g value clearly categorized them into two distinct groups with positive (near-zero) and negative g values (around −1) for the indolent and aggressive NHLs, respectively. Conclusions Distinct quantum metabolic values of −1 and 0 were noted in NHL. Aggressive NHL has a more negative value (or higher glucose sensitivity) than that of indolent and, thus, is more susceptible to extreme glucose variation.     

Introduction to the Proceedings of the 2nd World Molecular Imaging Congress

Purpose  To demonstrate the presence of endothelial dysfunction (ED) in asymptomatic patients with type 2 diabetes mellitus (DM) by using ¹³N-ammonia–positron emission tomography (PET). PET can identify ED by quantifying myocardial blood flow (MBF) during rest, cold pressor test (CPT), and pharmacologic stress. The endothelial-dependent vasodilation index (EDVI), myocardial flow reserve (MFR), and the percentage of the change between rest and CPT (%ΔMBF) are markers of endothelial function. Procedures  Thirty-nine subjects were studied (19 women and 20 men); 22 recently diagnosed type 2 diabetic patients and 17 healthy controls (HC). A three-phase ¹³N-ammonia–PET was performed. Results  Mean EDVI was 1.208 ± 0.34 vs. 1.55 ± 0.37 (diabetic vs. HC group, respectively) (p = 0.002), MFR was 2.803 ± 1.39 vs. 3.27 ± 0.72 (p = NS), and the %ΔMBF was 20 ± 34% vs. 55 ± 37% (p = 0.002). Rest MBF and CPT MBF were normalized to the rate pressure product (RPP). EDVI′ and %ΔMBF′ were calculated using the corrected values for the RPP. Mean EDVI′ was (0.864 ± 0.250 vs. 1.110 ± 0.238, p = 0.004) and mean %ΔMBF′ was (−8.2 ± 14.7% vs. 4.5 ± 12.1%, p = 0.005). Conclusions  Asymptomatic, recently diagnosed type 2 diabetes patients present ED that can be quantified by ¹³N-ammonia–PET.     

Radioisotopic Localization of 90Yttrium–Ibritumomab Tiuxetan in Patients with CD20+ Non-Hodgkin’s Lymphoma

Purpose   ⁹⁰Yttrium-ibritumomab-tiuxetan (Zevalin) is an effective treatment for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. The purpose of this study is to assess whether tissue and cellular localization of ⁹⁰Y-ibritumomab–tiuxetan determined by autoradiography and radioactivity localized to tumor tissue might enhance our understanding of the mechanism of action of radioimmunotherapy. Methods  Eight eligible patients had CD20+ NHL, a bulky peripheral lymph node, and were scheduled for ⁹⁰Y-ibritumomab–tiuxetan treatment. 2-Deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed prior to treatment and at 12 weeks after therapy for assessment of response. Bone marrow, lymph node, and blood samples were collected 114 ± 3 h after 14.8 MBq/kg ⁹⁰Y-ibritumomab-tiuxetan and processed for histology, scintillation counting, and microscopic autoradiography. Results  Pericellular membrane localization of ⁹⁰Y-ibritumomab–tiuxetan to lymphoma cells was observed by autoradiography in the involved areas of lymph node with absence of significant localization in histologically normal sections of bone marrow. Pericellular radioactivity and the highest quantitative radioactivity were observed in lymph node samples of responding patients. Conclusions   ⁹⁰Y-ibritumomab-tiuxetan localizes to the surface membrane of CD20+ lymphoma cells in affected lymph nodes. The patients with the highest quantitative concentration of radioactivity to the lymph node as determined by scintillation counting were observed to have a clinical and FDG-PET/CT response.     

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [11C]Metoclopramide

Purpose

To assess in healthy volunteers the whole-body distribution and dosimetry of [¹¹C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.

Procedures

Ten healthy volunteers (five women, five men) were intravenously injected with 387?±?49 MBq of [¹¹C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.

Results

The majority of the administered dose of [¹¹C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [¹¹C]metoclopramide was 1.69?±?0.26 μSv/MBq for female subjects and 1.55?±?0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81?±?0.23 μGy/MBq and 8.78?±?0.89 μGy/MBq) and the liver (6.80?±?0.78 μGy/MBq and 4.91?±?0.74 μGy/MBq) for female and male subjects, respectively.

Conclusions

[¹¹C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [¹¹C]metoclopramide was comparable to other ¹¹C-labeled PET tracers.

     

Quantitative Positron Emission Tomography Studies of the Serotonin Transporter in Humans Previously Treated with the Appetite Suppressants Fenfluramine or Dexfenfluramine

Purpose The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [¹¹C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters. Procedures Subjects previously treated with fenfluramines for weight loss (N = 15) and age-matched controls (N = 17) underwent PET studies with [¹¹C] McN5652. Global and regional distribution volumes (DVs) of [¹¹C] McN5652 were compared in the two subject groups using parametric statistical analyses. Results Compared to controls, subjects previously exposed to fenfluramines had significant reductions in [¹¹C]McN5652 binding in 14 of 15 regions of interest, more than four years after drug discontinuation. Conclusions These results are the first to provide direct evidence for fenfluramine-induced 5-HT neurotoxicity in humans.     

Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand

[¹¹C]MePPEP is a high affinity, CB₁ receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [¹¹C]MePPEP to quantify CB₁ receptors in human brain as distribution volume calculated with the “gold standard” method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability. After injection of [¹¹C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen at  60 min) and washed out very slowly. A two-tissue compartment model yielded values of distribution volume (which is proportional to receptor density) that were both well identified (SE 5%) and stable between 60 and 210 min. The simple measure of brain uptake (average concentration of radioactivity between 40 and 80 min) had good retest variability ( 8%) and moderate intersubject variability (16%, coefficient of variation). In contrast, distribution volume had two-fold greater retest variability ( 15%) and, thus, less precision. In addition, distribution volume had three-fold greater intersubject variability ( 52%). The decreased precision of distribution volume compared to brain uptake was likely due to the slow washout of radioactivity from brain and to noise in measurements of the low concentrations of [¹¹C]MePPEP in plasma. These results suggest that brain uptake can be used for within subject studies (e.g., to measure receptor occupancy by medications) but that distribution volume remains the gold standard for accurate measurements between groups.     

Evaluation of Rho-Kinase Activity in Mice Brain Using N-[11C]Methyl-hydroxyfasudil with Positron Emission Tomography

Purpose

Rho is a small molecular weight GTP-binding protein and works as a molecular shuttling switch between an active (GTP-bound) and inactive (GDP-bound) state. Rho is known to be involved in cell motility, cell adhesion, and cytokinesis through actin cytoskeleton reorganization. The GTP-bound form of Rho interacts with its specific downstream target, triggering intracellular signaling cascades. Rho effectors such as Rho-kinases have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Rho-kinase is thought to have an important role in the pathogenesis of a variety of neurological diseases because activation of the Rho/Rho-kinase pathway has been observed in various central nervous system disorders. Previous histochemical studies have shown multiple molecular mechanisms for the regulation of Rho-kinase. Neuroimaging of Rho/Rho-kinase has rarely been studied because of a lack of appropriate radiotracers. Recently, N-[¹¹C]methyl-hydroxyfasudil, a new radiotracer for positron emission tomography (PET), has been introduced to measure Rho-kinase activity. In this study, the regional distribution and kinetics of N-[¹¹C]methyl-hydroxyfasudil were investigated in the brains of mice.

Procedures

A 90-min dynamic scan was performed following intravenous infusion of N-[¹¹C]methyl-hydroxyfasudil.

Results

The uptake of N-[¹¹C]methyl-hydroxyfasudil reached a maximum within 5 min and gradually decreased in all organs. The standard uptake values (SUVs) in the brain, liver, and kidney on average between 30 to 60 min were 0.17?±?0.03, 0.76?±?0.18, and 0.62?±?0.18 and from 60 to 90 min were 0.15?±?0.01, 0.69?±?0.33, and 0.64?±?0.17, respectively. N-[¹¹C]Methyl-hydroxyfasudil showed a widespread distribution throughout the brain, with low levels of radioactivity. Radioactivity concentration in plasma at 90 min after injection of N-[¹¹C]methyl-hydroxyfasudil resulted in SUVs in the control and fasudil pretreatment of 0.0013 and 0.0023?±?0.0008, respectively. Compared to normal control mice, about twofold higher radioactivity concentration was observed in fasudil-pretreated mice. In a cold brain injury mouse model, accumulation of N-[¹¹C]methyl-hydroxyfasudil was slightly higher at the injury site than that at the control site, and the difference was statistically significant in the “24 h after injury” group (P?<?0.05).

Conclusions

These results suggest that following brain injury, N-[¹¹C]methyl-hydroxyfasudil binds to the active form of Rho-kinase. PET imaging using N-[¹¹C]methyl-hydroxyfasudil could provide new insights into the pathophysiology of a variety of neurological disorders including stroke, inflammatory diseases, demyelinating diseases, Alzheimer's disease, and neuropathic pain.     

Standardized Uptake Value Atlas: Characterization of Physiological 2-Deoxy-2-[<Superscript>18</Superscript>F]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose Uptake in Normal Tissues

Purpose The purpose of this study was to map the distribution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in organs of patients with no known abnormalities in those tissues. Procedures We measured maximum and mean standardized uptake values (SUV) from FDG-positron emission tomography (PET)/computed tomography (CT) obtained from 98 patients (48 males and 50 females). Results Significant uptake (mean SUV_mean > 2.5) was visualized in the cerebellum (8.0 ± 2.2), soft palate (2.92 ± 0.86), palatine tonsils (3.45 ± 1.4), lingual tonsils (3.08 ± 1.05), sublingual glands (3.3 ± 1.5), and testes (2.57 ± 0.56). Negative correlation for FDG uptake versus age was observed for the palatine tonsils, sublingual glands, and lungs (P < 0.001). Conclusion Better understanding of physiological uptake throughout the body is valuable for improved interpretive accuracy and should be useful for future semi-automated comparisons to a normal SUV database.     

Increasing Uptake Time in FDG-PET: Standardized Uptake Values in Normal Tissues at 1 versus 3 h

Objective  Positron emission tomography (PET) imaging at more than 1 h after 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) administration may result in less blood pool activity and possibly decreased normal FDG uptake in tissues such as liver. Lower normal background activity could be an important component of improved image contrast on delayed imaging. Increasing FDG uptake in normal organs, however, may mitigate the beneficial effects of blood pool clearance. The purpose of this study is to determine the normal tissue and blood pool FDG uptake at 1 and 3 h after injection. Subjects and methods  Ninety-nine patients with known or suspected malignancy referred for FDG-PET–computed tomography (CT) were retrospectively evaluated. PET imaging was performed at either 1 h (60 ± 15 min; n = 50) or at 3 h (180 ± 15 min; n = 49) after FDG administration. Normal tissue FDG uptake without involvement by malignancy or influenced by artifact (misregistration, “brown fat,” focal muscle uptake, focal atherosclerotic disease) was confirmed by inspection of both the PET and CT scans. Aortic blood pool, adipose tissue, bone marrow, cerebellum, liver, lungs, muscle, and spleen were quantitatively evaluated by CT-guided region of interest analysis in three contiguous slices. Mean standardized uptake values (SUVs) were analyzed using one-way analysis of variance. Results  Mean SUVs on the 3- versus 1-h images were significantly lower for aortic blood pool 13% (p < 0.0001) and adipose tissue 20% (p < 0.008). FDG uptake showed significant increases at 3 h compared to 1-h imaging in the cerebellum 40% (p < 0.0001), bone marrow 25% (p = 0.003), muscle 21% (p = 0.0004), and spleen 13% (p = 0.01). The liver and lung showed no significant differences (1%, p = 0.85; −2%, p = 0.62, respectively). Conclusions  On FDG imaging at 3 h compared to 1 h, significant changes were apparent, but the magnitude of changes was modest overall. Three-hour delayed imaging demonstrated significantly lower aortic blood pool and adipose tissue activity and significantly higher cerebellum, muscle, spleen, and bone marrow activity. Hepatic and lung activities were not significantly different. These results suggest that previously reported improvements in tumor image contrast with delayed imaging may be primarily due to cumulative FDG uptake within the tumor rather than reduction in normal background activity.     

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.     

Evaluation of left atrial functions by color tissue Doppler imaging in adults with body mass indexes ≥30 kg/m<Superscript>2</Superscript> versus those <30 kg/m<Superscript>2</Superscript>

Evaluation of atrial function has received less attention than that of the ventricle although normal atrial function is required for optimal overall cardiac function. Obesity is associated with increased cardiovascular morbidity and mortality. In this study, we compared left atrial functions in obese adults (body mass index = BMI ≥30 kg/m²) with those in non-obese adults (BMI <30 kg/m²) by color tissue Doppler parameters. There were 37 adults with BMI ≥30 kg/m² (mean age 36 ± 11 years) and 26 adults with BMI <30 kg/m² (mean age 35 ± 5 years). Mean BMI was 38 ± 6 kg/m² in the obese group whereas that was 24 ± 2 kg/m² in the non-obese group. For color tissue Doppler imaging, sample volumes were placed on the mid left atrium at the septum, lateral, inferior, and anterior walls. The peak systolic strain (S _s), peak systolic strain rate (SR_s), peak early diastolic SR (SR_e), peak late diastolic SR (SR_a), peak systolic tissue velocity (TV_s), peak early diastolic TV (TV_e) and peak late diastolic TV (TV_a) values were measured. For each measurement, values in three consecutive cardiac cycles were measured and then averaged. To simplify the analysis, the values at each wall were combined and averaged to obtain mean values. All left atrial systolic function parameters (S _s, SR_s, TV_s) were similar between the groups. In addition, there was no statistically significant difference at left atrial diastolic function parameters (SR_e, SR_a, TV_e, TV_a). We could not find any significant difference between obese and non-obese adults at left atrial functions assessed by color tissue Doppler parameters.