Rest/stress myocardial perfusion imaging by positron emission tomography with 18F-Flurpiridaz: A feasibility study in mice.

BACKGROUND: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. METHODS: Rest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7-8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. RESULTS: Tracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7 to 20.0 mL·cm-3·min-1, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL·cm-3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (rs) ranged between 0.478 and 0.681, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R2 ≥ 0.98). Notably, K1 and VT were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice. CONCLUSION: Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

Assessment of cholesterol homeostasis in the living human brain.

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18F-CHL-2205 (18F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer's disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.

Role of sex hormones in modulating myocardial perfusion and coronary flow reserve.

BACKGROUND: A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. METHODS: Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. RESULTS: Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. CONCLUSION: Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

When SUV Matters: FDG PET/CT at Baseline Correlates with Survival in Soft Tissue and Ewing Sarcoma.

INTRODUCTION: The role of positron-emission tomography/computed-tomography (PET/CT) in the management of sarcomas and as a prognostic tool has been studied. However, it remains unclear which metric is the most useful. We aimed to investigate if volume-based PET metrics (Tumor volume (TV) and total lesions glycolysis (TLG)) are superior to maximal standardized uptake value (SUVmax) and other metrics in predicting survival of patients with soft tissue and bone sarcomas. MATERIALS AND METHODS: In this retrospective cohort study, we screened over 52'000 PET/CT scans to identify patients diagnosed with either soft tissue, bone or Ewing sarcoma and had a staging scan at our institution before initial therapy. We used a Wilcoxon signed-rank to assess which PET/CT metric was associated with survival in different patient subgroups. Receiver-Operating-Characteristic curve analysis was used to calculate cutoff values. RESULTS: We identified a total of 88 patients with soft tissue (51), bone (26) or Ewing (11) sarcoma. Median age at presentation was 40 years (Range: 9-86 years). High SUVmax was most significantly associated with short survival (defined as <24 months) in soft tissue sarcoma (with a median and range of SUVmax 12.5 (8.8-16.0) in short (n = 18) and 5.5 (3.3-7.2) in long survival (≥24 months) (n = 31), with (p = 0.001). Similar results were seen in Ewing sarcoma (with a median and range of SUVmax 12.1 (7.6-14.7) in short (n = 6) and 3.7 (3.5-5.5) in long survival (n = 5), with (p = 0.017). However, no PET-specific metric but tumor-volume was significantly associated (p = 0.035) with survival in primary bone sarcomas (with a median and range of 217 cm3 (186-349) in short survival (n = 4) and 60 cm3 (22-104) in long survival (n = 19), with (p = 0.035). TLG was significantly inversely associated with long survival only in Ewing sarcoma (p = 0.03). DISCUSSION: Our analysis shows that the outcome of soft tissue, bone and Ewing sarcomas is associated with different PET/CT metrics. We could not confirm the previously suggested superiority of volume-based metrics in soft tissue sarcomas, for which we found SUVmax to remain the best prognostic factor. However, bone sarcomas should probably be evaluated with tumor volume rather than FDG PET activity.

A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2-Induced Glycolytic Reprogramming in Glioblastoma.

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

Potential Impact of Statins on Neuronal Stress Responses in Patients at Risk for Cardiovascular Disease.

BACKGROUND: Recent studies indicate that enhanced neuronal stress responses are associated with adverse cardiovascular outcomes. A chronic inflammatory state seems to mediate this detrimental neuro-cardiac communication. Statins are among the most widely prescribed medications in primary and secondary cardiovascular disease (CVD) prevention and not only lower lipid levels but also exhibit strong anti-inflammatory and neuroprotective effects. We therefore sought to investigate the influence of statins on neuronal stress responses in a patient cohort at risk for CVD. METHODS: 563 patients (61.5 ± 14.0 years) who underwent echocardiography and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were retrospectively identified. Metabolic activity of the amygdala, a part of the brain's salience network, was quantified by 18F-FDG uptake, while normal cardiac morphology and function were assured by echocardiography. Vertebral bone marrow metabolism, a marker of inflammatory activity, was measured by 18F-FDG PET. RESULTS: Increased neuronal stress responses were associated with an increased inflammatory activity in the bone marrow (r = 0.152, p = 0.015) as well as with a subclinical reduction in left ventricular ejection fraction (LVEF, r = -0.138, p = 0.025). In a fully-adjusted linear regression model, statin treatment was identified as an independent, negative predictor of amygdalar metabolic activity (B-coefficient -0.171, p = 0.043). CONCLUSIONS: Our hypothesis-generating investigation suggests a potential link between the anti-inflammatory actions of statins and reduced neuronal stress responses which could lead to improved cardiovascular outcomes. The latter warrants further studies in a larger and prospective population.

Age- and sex-dependent changes of resting amygdalar activity in individuals free of clinical cardiovascular disease.

PURPOSE: Amygdalar metabolic activity was shown to independently predict cardiovascular outcomes. However, little is known about age- and sex-dependent variability in neuronal stress responses among individuals free of cardiac disease. This study sought to assess age- and sex-specific differences of resting amygdalar metabolic activity in the absence of clinical cardiovascular disease. METHODS: Amygdalar metabolic activity was assessed in 563 patients who underwent multimodality imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography and echocardiography for the evaluation of cardiac function. RESULTS: After exclusion of 294 patients with structural or functional cardiovascular pathologies, 269 patients (128 women) remained in the final population. 18F-FDG amygdalar activity significantly decreased with age in men (r = - 0.278, P = 0.001), but not in women (r = 0.002, P = 0.983). Similarly, dichotomous analysis confirmed a lower amygdalar activity in men ≥ 50 years as compared to those < 50 years of age (0.79 ± 0.1 vs. 0.84 ± 0.1, P = 0.007), which was not observed in women (0.81 ± 0.1 vs. 0.82 ± 0.1, P = 0.549). Accordingly, a fully adjusted linear regression analysis identified age as an independent predictor of amygdalar activity only in men (B-coefficient - 0.278, P = 0.001). CONCLUSION: Amygdalar activity decreases with age in men, but not in women. The use of amygdalar activity for cardiovascular risk stratification merits consideration of inherent age- and sex-dependent variability.

Quantification of perivascular inflammation does not provide incremental prognostic value over myocardial perfusion imaging and calcium scoring.

AIMS: Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)-based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). METHODS AND RESULTS: A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > - 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220-6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218-3.686, p = 0.008; and HR 2.071, 95% CI: 1.111-3.861, p = 0.022). CONCLUSION: FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex.

[11C]mHED PET follows a two-tissue compartment model in mouse myocardium with norepinephrine transporter (NET)-dependent uptake, while [18F]LMI1195 uptake is NET-independent.

PURPOSE: Clinical positron emission tomography (PET) imaging of the presynaptic norepinephrine transporter (NET) function provides valuable diagnostic information on sympathetic outflow and neuronal status. As data on the NET-targeting PET tracers [11C]meta-hydroxyephedrine ([11C]mHED) and [18F]LMI1195 ([18F]flubrobenguane) in murine experimental models are scarce or lacking, we performed a detailed characterization of their myocardial uptake pattern and investigated [11C]mHED uptake by kinetic modelling. METHODS: [11C]mHED and [18F]LMI1195 accumulation in the heart was studied by PET/CT in FVB/N mice. To test for specific uptake by NET, desipramine, a selective NET inhibitor, was administered by intraperitoneal injection. [11C]mHED kinetic modelling with input function from an arteriovenous shunt was performed in three mice. RESULTS: Both tracers accumulated in the mouse myocardium; however, only [11C]mHED uptake was significantly reduced by excess amount of desipramine. Myocardial [11C]mHED uptake was half-saturated at 88.3 nmol/kg of combined mHED and metaraminol residual. After [11C]mHED injection, a radiometabolite was detected in plasma and urine, but not in the myocardium. [11C]mHED kinetics followed serial two-tissue compartment models with desipramine-sensitive K1. CONCLUSION: PET with [11C]mHED but not [18F]LMI1195 provides information on NET function in the mouse heart. [11C]mHED PET is dose-independent in the mouse myocardium at < 10 nmol/kg of combined mHED and metaraminol. [11C]mHED kinetics followed serial two-tissue compartment models with K1 representing NET transport. Myocardial [11C]mHED uptake obtained from PET images may be used to assess cardiac sympathetic integrity in mouse models of cardiovascular disease.

Myocardial 18F-FDG Uptake Pattern for Cardiovascular Risk Stratification in Patients Undergoing Oncologic PET/CT.

OBJECTIVE: Positron emission tomography/computed tomography with 18F-fluorodeoxy-glucose (18F-FDG-PET/CT) has become the standard staging modality in various tumor entities. Cancer patients frequently receive cardio-toxic therapies. However, routine cardiovascular assessment in oncologic patients is not performed in current clinical practice. Accordingly, this study sought to assess whether myocardial 18F-FDG uptake patterns of patients undergoing oncologic PET/CT can be used for cardiovascular risk stratification. METHODS: Myocardial 18F-FDG uptake pattern was assessed in 302 patients undergoing both oncologic whole-body 18F-FDG-PET/CT and myocardial perfusion imaging by single-photon emission computed tomography (SPECT-MPI) within a six-month period. Primary outcomes were myocardial 18F-FDG uptake pattern, impaired myocardial perfusion, ongoing ischemia, myocardial scar, and left ventricular ejection fraction. RESULTS: Among all patients, 109 (36.1%) displayed no myocardial 18F-FDG uptake, 77 (25.5%) showed diffuse myocardial 18F-FDG uptake, 24 (7.9%) showed focal 18F-FDG uptake, and 92 (30.5%) had a focal on diffuse myocardial 18F-FDG uptake pattern. In contrast to the other uptake patterns, focal myocardial 18F-FDG uptake was predominantly observed in patients with myocardial abnormalities (i.e., abnormal perfusion, impaired LVEF, myocardial ischemia, or scar). Accordingly, a multivariate logistic regression identified focal myocardial 18F-FDG uptake as a strong predictor of abnormal myocardial function/perfusion (odds ratio (OR) 5.32, 95% confidence interval (CI) 1.73-16.34, p = 0.003). Similarly, focal myocardial 18F-FDG uptake was an independent predictor of ongoing ischemia and myocardial scar (OR 4.17, 95% CI 1.53-11.4, p = 0.005 and OR 3.78, 95% CI 1.47-9.69, p = 0.006, respectively). CONCLUSIONS: Focal myocardial 18F-FDG uptake seen on oncologic PET/CT indicates a significantly increased risk for multiple myocardial abnormalities. Obtaining and taking this information into account will help to stratify patients according to risk and will reduce unnecessary cardiovascular complications in cancer patients.

Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF).

BACKGROUND: Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown. METHODS: A total of 1367 patients (352 women, mean age 63.1 ± 11.6 years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization. RESULTS: The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing-a surrogate marker for autonomic dysregulation-were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6 years, women with snLVEF experienced more often a MACE than women with normal (55-65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76). CONCLUSION: snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

Sex-dependent association between inflammation, neural stress responses, and impaired myocardial function.

PURPOSE: Evidence to date has failed to reveal unique female determinants of cardiovascular disease. However, a strong association was recently observed between increased metabolic activity in the amygdala, a neural centre involved in the processing of emotions, and impaired myocardial function in women, but not in men. Given the stronger immune responses in females, we sought to retrospectively investigate the interaction between inflammation, perceived stress, and myocardial injury. METHODS: Overall, 294 patients (mean age 66.9 ± 10.0 years, 28.6% women) underwent both, 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography for the assessment of cardiac function, bone marrow metabolism (surrogate marker of inflammation), and resting amygdalar activity. RESULTS: A positive association was found between amygdalar metabolism and 18F-FDG bone marrow uptake in women (r = 0.238, p = 0.029), but not in men (r = 0.060, p = 0.385). Linear regression models selected both, abnormal left ventricular ejection fraction (LVEF) and abnormal myocardial perfusion, as significant indicators of an increased amygdalar activity in women (B-coefficient LVEF, - 0.096; p = 0.021; abnormal myocardial perfusion, 3.227; p = 0.043), but not in men (bone marrow p = 0.076; abnormal myocardial perfusion p = 0.420). Accordingly, an interaction term consisting of sex and LVEF/abnormal myocardial perfusion was significant (p = 0.043 and p = 0.015, respectively). CONCLUSIONS: Upregulated amygdalar metabolism is associated with an enhanced inflammatory state in female patients with impaired cardiac function. Given that enhanced activity of the limbic system is associated with worse cardiovascular outcomes, our study suggests that a focus on inflammatory markers and indicators of distress might help to tailor cardiovascular risk assessment and therapy towards the female cardiovascular phenotype.

Sex Differences in the Association between Inflammation and Ischemic Heart Disease.

BACKGROUND: Inflammation plays a fundamental role in mediating all stages of atherosclerosis. Given the higher prevalence of inflammatory rheumatologic conditions in women and the female propensity towards worse cardiovascular outcomes, refined strategies are needed to better identify the high-risk female cardiovascular phenotype. OBJECTIVES: This article aims to assess sex-specific links between inflammatory processes and the development and progression of ischemic heart disease. PATIENTS AND METHODS: The relationship between vertebral bone marrow metabolism-a marker of inflammation-and myocardial injury was retrospectively assessed in 294 patients (28.6% women, mean age: 66.9 ± 10.0 years) who underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). RESULTS: A significant increase in 18F-FDG bone marrow uptake was observed in women with impaired myocardial perfusion (SPECT-MPI) as compared to women with normal myocardial perfusion (standardized uptake value [SUV]: 2.2 ± 1.2 vs. 1.7 ± 0.5, p = 0.013), while no such difference was observed in men (SUV: 1.6 ± 0.8 vs. 1.6 ± 0.4, p = 0.372). Furthermore, a significant inverse correlation between left ventricular ejection fraction (LVEF) and bone marrow metabolism was seen in women (r = -0.229, p = 0.037), but not in men (r = -0.075, p = 0.289). Accordingly, in women, but not in men, bone marrow activity was identified as an independent predictor of both, reduced LVEF (ß-coefficient, -4.537; p = 0.040) and impaired myocardial perfusion (ß-coefficient, 0.138; p = 0.014). CONCLUSION: A strong link between bone marrow metabolism and impaired myocardial function and perfusion was observed in women, but not in men. Our data suggest that novel biomarkers of inflammation might help to identify women at risk for ischemic cardiomyopathy and to tailor disease management to the female cardiovascular phenotype.

Evaluation of 18F-UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain.

UNLABELLED: Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. (18)F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. METHODS: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a ß-microprobe system. (18)F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). RESULTS: Brain uptake of (18)F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for (18)F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on Vt was measured. In control animals the whole-brain Vt was 9.76 ± 0.52 mL/cm(3) (mean ± SD; n = 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of (18)F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously). CONCLUSION: Our results indicated that (18)F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of (18)F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

Comparison of PET template-based and MRI-based image processing in the quantitative analysis of C11-raclopride PET.

BACKGROUND: Quantitative measures of 11C-raclopride receptor binding can be used as a correlate of postsynaptic D2 receptor density in the striatum, allowing 11C-raclopride positron emission tomography (PET) to be used for the differentiation of Parkinson's disease from atypical parkinsonian syndromes. Comparison with reference values is recommended to establish a reliable diagnosis. A PET template specific to raclopride may facilitate direct computation of parametric maps without the need for an additional MR scan, aiding automated image analysis. METHODS: Sixteen healthy volunteers underwent a dynamic 11C-raclopride PET and a high-resolution T1-weighted MR scan of the brain. PET data from eight healthy subjects was processed to generate a raclopride-specific PET template normalized to standard space. Subsequently, the data processing based on the PET template was validated against the standard magnetic resonance imaging (MRI)-based method in 8 healthy subjects and 20 patients with suspected parkinsonian syndrome. Semi-quantitative image analysis was performed in Montreal Neurological Institute (MNI) and in original image space (OIS) using VOIs derived from a probabilistic brain atlas previously validated by Hammers et al. (Hum Brain Mapp, 15:165-174, 2002). RESULTS: The striatal-to-cerebellar ratio (SCR) of 11C-raclopride uptake obtained using the PET template was in good agreement with the MRI-based image processing method, yielding a Lin's concordance coefficient of 0.87. Bland-Altman analysis showed that all measurements were within the ±1.96 standard deviation range. In all 20 patients, the PET template-based processing was successful and manual volume of interest optimization had no further impact on the diagnosis of PD in this patient group. A maximal difference of <5% was found between the measured SCR in MNI space and OIS. CONCLUSIONS: The PET template-based method for automated quantification of postsynaptic D2 receptor density is simple to implement and facilitates rapid, robust and reliable image analysis. There was no significant difference between the SCR values obtained with either PET- or MRI-based image processing. The method presented alleviates the clinical workflow and facilitates automated image analysis.

Metabolism of no-carrier-added 2-[18F]fluoro-L-tyrosine in rats.

BACKGROUND: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas. METHODS: No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant. RESULTS: The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, no-carrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions. CONCLUSION: This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma.