Faculty Bibliography

PURPOSE: [(18)F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [(18)F]FPEB in the human brain. METHODS: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 +/- 32 MBq [(18)F]FPEB. Four methods were used to estimate volume of distribution (V T): equilibrium analysis (EQ) using arterial (EQA) or venous input data (EQV), MA1, and a two-tissue compartment model (2 T). Binding potential (BP ND) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V T and BP ND were calculated for each method. Venous blood measurements (C V) were compared with arterial input (C A) to examine their usability in EQ analysis. RESULTS: Regional V T estimated by the four methods displayed a high degree of agreement (r (2) ranging from 0.83 to 0.99 among the methods), although EQA and EQV overestimated V T by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V T were 11 % by EQA, 12 % by EQV, 14 % by MA1 and 14 % by 2 T. Regional BP ND also agreed well among the methods and mean aTRV of BP ND was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [(18)F]FPEB were well matched during equilibrium (C V = 1.01 . C A, r (2) = 0.95). CONCLUSION: [(18)F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [(18)F]FPEB is an excellent PET imaging tracer for mGluR5 in humans.

BACKGROUND: Previous work in healthy non-human primates and humans has shown that social status correlates positively with dopamine 2/3 receptor (D2/3R) availability imaged with antagonist radioligands and positron emission tomography (PET). Further work in non-human primates suggests that this relationship is disrupted by chronic cocaine administration. This exploratory study examined the relationship between social status and D2/3R availability in healthy (HH) and cocaine dependent (CD) humans using the D3-preferring, agonist radioligand, [11C](+)PHNO. METHODS: Sixteen HH and sixteen CD individuals completed the Barratt Simplified Measure of Social Status (BSMSS) and underwent [11C](+)PHNO scanning to measure regional brain D2/3R binding potentials (BPND). Correlations between BPND and BSMSS scores were then assessed within each group. RESULTS: Within HH and CD groups, inverse associations between BSMSS score and BPND were observed in the substantia nigra/ventral tegmental area (SN/VTA) and the ventral striatum, and for the CD group alone, the amygdala. After adjusting for body mass index and age, negative correlations remained significant in the SN/VTA for HH and in the amygdala for CD subjects. CONCLUSION: These preliminary data utilizing a dopamine agonist tracer demonstrate, for the first time, an inverse association between social status and D2/3R availability in the D3R rich extrastriatal regions of HH and CD humans.

INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6+/-2.6, BMI 21.6+/-2.7kg/m(2); 5 F: age 25.4+/-2.1, BMI 22.1+/-1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15 degrees C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0+/-0.3 vs. cold 1.1+/-0.3, p=0.31; BAT/muscle DVR: RT 2.3+/-0.7 vs. cold 2.5+/-0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.

PURPOSE: Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study was to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. METHODS: Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multiparametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions of interest were manually placed on tumor and benign prostate tissue. Blood activity was extracted from a region of interest placed on the femoral artery on PET images. FDG data were analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding seemed irreversible and distribution volume VT (reversible graphical analysis) when FDG binding seemed reversible given the presence of washout. RESULTS: Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In 2 cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs 0.006 and 0.019 vs 0.008 mL/cm per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm). CONCLUSIONS: Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking advantage of inclusion of the femoral arteries in the FOV, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.

Norepinephrine plays a central role in emotional regulation. Further, the predisposition and maintenance of eating disorders have been linked to the central NET system. However, the relationship between emotional eating and NET availability has not yet been investigated. Therefore we investigated the NET status in heavily obese patients with regard to emotional eating, expressed emotion and external eating. We studied 10 obese, non-depressive subjects (OB, body mass index (BMI) 42.4+3.7 kg/m2, age 34.4+9.0 years, 4 female) and 10 control subjects (HC, BMI 23.9+2.5 kg/m2, age 33.3+10 years, 4 female) with C-11 methylreboxetine (MRB) and PET. The NET binding potential (BP) were obtained by individual MR-based volume-of-interest (VOI) analysis (PMOD 3.4). Prior to scanning, participants completed the Difficulties in Emotion Regulation Scale (DERS); the Brief Dyadic Scale of Expressed Emotion (BDSEE) Criticism (CC); emotional over involvement (EOI); and the Dutch Eating Behavior Questionnaire's (DEBQ) External Eating (EE) subscale. The BDSEE-CC differed significantly between OB and HC (p=0.03) whereas there was no group differences regarding the remaining psychometrical total and/or subscale scores or the BP in the distinct brain areas. BP was associated with the BDSEE-CC score in HC, but not in OB in the thalamus (HC, right thalamus: r=0.77; p=0.01; HC, left thalamus: r=0.78; p=0.01). In contrast, DERS total score correlates significantly in OB but not in HC with BP in the thalamic regions (OB, DERS total score, left thalamus: r=0.69; p=0.04) and reward-related regions such as nucleus accumbens (OB: r=-0.67; p=0.05). DEBQ-EE subscale again showed thalamic involvement in OB (r=0.81; p<0.001). The negative effect criticism (BDSEE-CC) was found to be the only psychometrical subscore that significantly differed between OB and HC. The association of central NET availability and emotional eating scores point to the suggestion that NE dysfunction in brain regions crucial for information processing might !

Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject's mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci.

11C-(+)-4-propyl-9-hydroxynaphthoxazine (11C-(+)-PHNO) is an agonist radioligand for imaging dopamine D2 and D3 receptors in the human brain with PET. In this study we evaluated the reproducibility of 11C-(+)-PHNO binding parameters using a within-day design and assessed parametric imaging methods. METHODS: Repeated studies were performed in 8 subjects, with simultaneous measurement of the arterial input function and plasma free fraction. Two 11C-(+)-PHNO scans for the same subject were separated by 5.4 +/- 0.7 h. After compartment models were evaluated, 11C-(+)-PHNO volumes of distribution (VT) and binding potentials relative to the concentration of tracer in plasma (BPP), nondisplaceable tracer in tissue (BPND), and free tracer in tissue (BPF) were quantified using the multilinear analysis MA1 method, with the cerebellum as the reference region. Parametric images of BPND were also computed using the simplified reference tissue model (SRTM) and SRTM2. RESULTS: The test-retest variability of 11C-(+)-PHNO BPND was 9% in D2-rich regions (caudate and putamen). Among D3-rich regions, variability was low in the pallidum (6%) but higher in substantia nigra (19%), thalamus (14%), and hypothalamus (21%). No significant mass carry-over effect was observed in D3-rich regions, although a trend in BPND was present in the substantia nigra (-14% +/- 15%). Because of the relatively fast kinetics, low-noise BPND parametric images were obtained with both SRTM and SRTM2 without spatial smoothing. CONCLUSION: 11C-(+)-PHNO can be used to compute low-noise parametric images in both D2- and D3-rich regions in humans.