Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA.

PURPOSE: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. METHODS: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. RESULTS: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting-based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). CONCLUSION: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers.

Impact of the lower energy threshold on the NEMA NU2-2001 count-rate performance of a LSO based PET-CT scanner.

UNLABELLED: The aim of this study was to investigate the impact of the lower energy threshold (LET) on the NEMA NU2-2001 count-rate performance of a LSO-based PET scanner (Siemens PET-CT Biograph Sensation 16). The quantitative measurements were focused on three different aspects: noise equivalent count rate (NEC), scatter fraction, and absolute sensitivity. METHODS: According to the NEMA-NU2-2001 protocol count-rate-performance (NEC-2R, scatter fraction) and sensitivity were evaluated performing serial measurements at LETs of 350, 375, 400, 410, 420, 430, 440, and 450 keV (the upper energy threshold was fixed to 650 keV). NEMA protocols were adapted to account for the intrinsic radioactivity of (176)Lu in the LSO crystals. RESULTS: Up to a radioactivity concentration of 8 kBq/ml the highest NEC-rates were obtained at an LET of 410 keV, between 8 and 20 kBq/ml at an LET of 420 keV and above 20 kBq/ml at an LET of 430 keV. The overall NEC maximum was 67 kcps at 430 keV (at 28 kBq/ml). The minimum scatter fraction was measured at a radioactivity concentration of approximately 0.5 kBq/ml. The scatter fraction decreased continuously from 45% at an energy threshold of 350 keV to 24% at 450 keV. The maximum sensitivity of 5.8 kcps/MBq, was obtained at an LET of 350 keV and the minimum sensitivity of 4.2 kcps/MBq at an LET of 450 keV. At the LET with the maximum NEC-rate (430 keV) the sensitivity was 4.8 kcps/MBq. CONCLUSION: The optimal count-rate performance of the LSO-based PET system was found at LETs between 410 keV and 430 keV depending on the actual radioactivity concentration placed in the scanner. A global maximum in NEC count rate was obtained at an LET of 430 keV.

Phased attenuation correction in respiration correlated computed tomography/positron emitted tomography.

The motion of lung tumors with respiration causes difficulties in the imaging with computed tomography (CT) and positronemitted tomography (PET). Since an accurate knowledge of the position of the tumor and the surrounding tissues is needed for radiation treatment planning, it is important to improve CT/PET image acquisition. The purpose of this study was to evaluate the potential to improve image acquisition using phased attenuation correction in respiration correlated CT/PET, where data of both modalities were binned retrospectively. Respiration correlated scans were made on a Siemens Biograph Sensation 16 CT/PET scanner which was modified to make a low pitch CT scan and list mode PET scan possible. A lollipop phantom was used in the experiments. The sphere with a diameter of 3.1 cm was filled with approximately 20 MBq 18F-FDG. Three longitudinal movement amplitudes were tested: 2.5, 3.9, and 4.8 cm. After collection of the raw CT data, list mode PET data, and the respiratory signal CT/PET images were binned to ten phases with the help of in-house-built software. Each PET phase was corrected for attenuation with CT data of the corresponding phase. For comparison, the attenuation correction was also performed with nonrespiration correlated (non-RC) CT data. The volume and the amplitude of the movement were calculated for every phaseof both the CT and PET data (with phased attenuation correction). Maximum and average activity concentrations were compared between the phased and nonphased attenuation corrected PET. With a standard non-RC CT/PET scan, the volume was underestimated by as much as 46% in CT and the PET volume was overestimated to 370%. The volumes found with RC-CT/PET scanning had average deviations of 1.9% (+/- 4.8%) and 1.5% (+/- 3.4%) from the actual volume, for the CT and PET volumes, respectively. Evaluation of the maximum activity concentration showed a clear displacement in the images with non-RC attenuation correction, and activity values were on average14% (+/- 12%) lower than with phased attenuation correction. The standard deviation of the maximum activity values found in the different phases was a factor of 10 smaller when phased attenuation correction was applied. In this phantom study, we have shown that a combination of respiration correlated CT/PET scanning with application of phased attenuation correction can improve the imaging of moving objects and can lead to improved volume estimation and a more precise localization and quantification of the activity.

Combined 18F-FDG-PET/CT imaging of the head and neck. An approach to metal artifact correction.

UNLABELLED: PET/CT imaging is particularly promising for head/neck malignancies, but dental implants lead to biased CT attenuation and PET activity values following CT-based attenuation correction (CT-AC). OBJECTIVE: Here, we implement a metal artifact correction procedure (MAR) as part of the CT-AC for PET/CT imaging. RESULTS: Phantom studies indicate a maximum quantitative bias in CT and PET of 1000 HU and 30 %, which is reduced to 230 HU and 6 %, respectively following MAR. These results were verified in selected patients. CONCLUSION: Artifacts and biases from dental implants can be reduced in PET/CT imaging by applying a simple MAR as part of the CT-AC.

Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function.

BACKGROUND: Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. METHODS AND RESULTS: We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (P:<0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. CONCLUSIONS: The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia.

OBJECTIVES: The present study evaluates the impact of total cholesterol (TC) and its subfractions on coronary flow reserve (CFR), an index of the integrated function of the coronary circulation, in asymptomatic subjects. BACKGROUND: Endothelial dysfunction of the coronary microcirculation has been reported in asymptomatic subjects with hypercholesterolemia. METHODS: Using oxygen-15-labeled water and positron emission tomography, myocardial blood flow (MBF, in ml/min per g) was measured at rest and during intravenous adenosine (140 microg/kg body weight per min) in 80 asymptomatic nonsmoking men: group 1 (n = 61; age 45 +/- 7 years) had normal TC (< or =6.5 mmol/liter or < or =250 mg/dl) and group 2 (n = 19; age 48 +/- 10 years) had elevated TC. RESULTS: Total cholesterol were 5.1 +/- 0.8 and 7.2 +/- 0.7 mmol/liter in groups 1 and 2 (p < 0.0005), respectively; low density lipoprotein (LDL) cholesterol levels were 3.2 +/- 0.8 and 4.9 +/- 0.7 mmol/liter (p < 0.0005); high density lipoprotein (HDL) cholesterol levels were 1.1 +/- 0.3 and 1.0 +/- 0.4 mmol/liter (p = NS); and triglyceride levels were 1.8 +/- 1.3 and 3.0 +/- 1.8 mmol/liter (p < 0.005). Groups 1 and 2 did not differ with regard to MBF at rest (0.87 +/- 0.14 vs. 0.84 +/- 0.14), MBF during adenosine (3.63 +/- 1.02 vs. 3.30 +/- 0.86) or CFR (4.23 +/-1.29 vs. 3.95 +/- 0.93). A significant but weak correlation was found between CFR and HDL in group 1 (r = 0.29, p < 0.05), but not in group 2. In contrast, a significant inverse correlation between LDL and CFR was found in group 2 (r = -0.61, p < 0.05), but not in group 1. CONCLUSIONS: Low density lipoprotein cholesterol but not TC correlated inversely with CFR in hypercholesterolemic subjects. Thus, LDL-induced coronary microvascular dysfunction could play an important role in the pathogenesis of coronary artery disease and its complications.

Motion correction in PET/CT.

Motion in PET/CT leads to artifacts in the reconstructed PET images due to the different acquisition times of positron emission tomography and computed tomography. The effect of motion on cardiac PET/CT images is evaluated in this study and a novel approach for motion correction based on optical flow methods is outlined. The Lukas-Kanade optical flow algorithm is used to calculate the motion vector field on both simulated phantom data as well as measured human PET data. The motion of the myocardium is corrected by non-linear registration techniques and results are compared to uncorrected images.

Imaging small animals with positron emission tomography.

During the past few years many research centers have successfully applied their knowledge of positron emission tomography (PET) to construct PET scanners which are dedicated to image small animals such as rats and mice. Although there are many in-house built systems which are used in laboratory environments, only a few of them are commercially available at this time. This review will give an overview of dedicated animal PET systems with their technical description and main physical characteristics. Graphical analysis of spatial resolution against absolute sensitivity allows a comparison of the most important characteristics of each camera. The quadHIDAC, a PET scanner recently installed at the Department of Nuclear Medicine, University Hospital Münster, acquires images with sub-millimeter spatial resolution. A (18)F-FDG whole body image of a mouse with small structures like the left ventricle of the heart clearly visualized, demonstrates its excellent spatial resolution.

Evaluation of respiratory and cardiac motion correction schemes in dual gated PET/CT cardiac imaging.

PURPOSE: Cardiac imaging suffers from both respiratory and cardiac motion. One of the proposed solutions involves double gated acquisitions. Although such an approach may lead to both respiratory and cardiac motion compensation there are issues associated with (a) the combination of data from cardiac and respiratory motion bins, and (b) poor statistical quality images as a result of using only part of the acquired data. The main objective of this work was to evaluate different schemes of combining binned data in order to identify the best strategy to reconstruct motion free cardiac images from dual gated positron emission tomography (PET) acquisitions. METHODS: A digital phantom study as well as seven human studies were used in this evaluation. PET data were acquired in list mode (LM). A real-time position management system and an electrocardiogram device were used to provide the respiratory and cardiac motion triggers registered within the LM file. Acquired data were subsequently binned considering four and six cardiac gates, or the diastole only in combination with eight respiratory amplitude gates. PET images were corrected for attenuation, but no randoms nor scatter corrections were included. Reconstructed images from each of the bins considered above were subsequently used in combination with an affine or an elastic registration algorithm to derive transformation parameters allowing the combination of all acquired data in a particular position in the cardiac and respiratory cycles. Images were assessed in terms of signal-to-noise ratio (SNR), contrast, image profile, coefficient-of-variation (COV), and relative difference of the recovered activity concentration. RESULTS: Regardless of the considered motion compensation strategy, the nonrigid motion model performed better than the affine model, leading to higher SNR and contrast combined with a lower COV. Nevertheless, when compensating for respiration only, no statistically significant differences were observed in the performance of the two motion models considered. Superior image SNR and contrast were seen using the affine respiratory motion model in combination with the diastole cardiac bin in comparison to the use of the whole cardiac cycle. In contrast, when simultaneously correcting for cardiac beating and respiration, the elastic respiratory motion model outperformed the affine model. In this context, four cardiac bins associated with eight respiratory amplitude bins seemed to be adequate. CONCLUSIONS: Considering the compensation of respiratory motion effects only, both affine and elastic based approaches led to an accurate resizing and positioning of the myocardium. The use of the diastolic phase combined with an affine model based respiratory motion correction may therefore be a simple approach leading to significant quality improvements in cardiac PET imaging. However, the best performance was obtained with the combined correction for both cardiac and respiratory movements considering all the dual-gated bins independently through the use of an elastic model based motion compensation.

Small animal PET in preclinical studies: opportunities and challenges.

The process of drug and molecular imaging development is strongly influenced by the revolution of non-invasive imaging techniques. Small animal positron emission tomography (PET) has the potential to accelerate and streamline drug and molecular imaging discovery and development by preselection of suitable candidate molecules. Due to its significantly improved spatial resolution and its quantitative nature, compared to other techniques small animal PET can be employed to bridge the in vitro, through to preclinical and clinical imaging in humans.

Elastic surface contour detection for the measurement of ejection fraction in myocardial perfusion SPET.

The aim of this study was to investigate the use of an automated three-dimensional myocardial contour detection method using elastic surfaces for the assessment of left ventricular ejection fraction (EF) from electrocardiographically (ECG) triggered myocardial perfusion single-photon emission tomography (SPET). The validity of this method was studied on the basis of both phantom measurements and patient studies. Phantom measurements were performed using an elastic phantom of the left ventricle simulating a beating heart, with a simulated EF ranging from 10% to 78%. The data from 27 patients who had undergone both ECG-triggered myocardial perfusion SPET and planar gated radionuclide ventriculography (RNV) were used to compare the EF derived from the SPET data with the automated contour detection method and the EF derived from the RNV data with standard analysis software. EF values as measured by RNV ranged from 11% to 68%. The overall accuracy of the automated contour detection method proved to be very high. In the phantom study the deviation of the measured EF from the reference values was less than 4% for all of the simulated EFs. The studies on the patient data yielded a correlation coefficient (Pearson) greater than 0.94 as compared with planar RNV. Intra- and inter-observer reproducibility was high, with correlation coefficients exceeding 0.97. It is concluded that the proposed method allows accurate, reproducible and fast measurement of the left ventricular EF on the basis of myocardial perfusion SPET.

Clinical evaluation of no-carrier-added meta-[123I]iodobenzylguanidine for myocardial scintigraphy.

In clinical and research studies, images obtained using carrier-added meta-[123I]iodobenzylguanidine (c.a. [123I]MIBG) have shown quite variable quality, with varying levels of uptake in lung, liver and mediastinum; this is a significant problem for quantification of the myocardial uptake by means of region ratios. First experimental and preliminary human data in respect of no-carrier-added (n.c.a.) [123I]MIBG are indicative of improved imaging quality. The aim of the present study was to evaluate the clinical value of myocardial scintigraphy with n.c.a. [123I]MIBG in patients with tachyarrhythmias. The study population comprised 24 patients with tachyarrhythmogenic diseases routinely studied by cardiac single-photon emission tomography (SPET) with [123I]MIBG. Twelve of the 24 patients were studied with c.a. [123I]MIBG (seven females and five males; mean age 42+/-13 years, range 20-60 years), whereas the other 12 were studied with n.c.a. [123I]MIBG (ten females, two males; mean age 41+/-11 years, range 18-60 years, P=NS). For quantification of the specific uptake in the different organs, count ratios were calculated on SPET images acquired 4 h p.i. Visual analysis of all [123I]MIBG scans showed improved image quality (improved contrast between heart and neighbouring organs) in n.c.a. studies as compared with c.a. studies. A significantly higher heart/left atrial blood ratio was found in the n.c.a. studies as compared with the c.a. studies (10.3+/-3.2 vs 5.3+/-1.3, P=0.0003); furthermore, significantly higher heart/lung and heart/liver ratios (2.5+/-0.6 vs 1.5+/-0.3, P=0.0002, and 0.8+/-0.2 vs 0.6+/-0.1, P=0.0006, respectively) were obtained in the c.a. studies, whereas lung/left atrial blood and liver/left atrial blood ratios showed no significant differences (4.2+/-1.3 vs 3.6+/-1.1, P=0.39, and 13.7+/-5.2 vs 9.6+/-2.2, P=0.21, respectively). In conclusion, the use of n.c.a. [123I]MIBG yields a significantly higher myocardial uptake associated with improvement in contrast between the heart and neighbouring organs and is therefore superior to the commercially available c.a. [123I]MIBG for use in clinical and research studies of the myocardial presynaptic sympathetic nervous system. Furthermore, our data indicate that for quantification the use of a left atrial blood reference region of interest, which is only available on SPET studies, is to be recommended.

Pulmonary beta adrenoceptor density in arrhythmogenic right ventricular cardiomyopathy and idiopathic tachycardia.

OBJECTIVE: In recent in vivo studies using positron emission tomography (PET) our group demonstrated that the myocardial beta adrenoceptor (betaAR) density is reduced in arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow tract tachycardia (RVO-VT) associated with an increased presynaptic catecholamine washout. It was hypothesised that the reduction of myocardial betaAR density is secondary to an increase of local catecholamines in the myocardium resulting from the presynaptic dysfunction since circulating plasma catecholamines were demonstrated to be unchanged in these conditions. To further prove this hypothesis of an organ-limited adrenergic nervous dysfunction of the heart, this study aimed to investigate betaAR density in another thoracic organ, the lung. METHODS: Pulmonary and myocardial betaAR density was measured in 7 ARVC patients, 8 RVO-VT patients and in a group of healthy controls (n = 13) using the non-selective beta-blocker [11C]-CGP 12177 and PET. RESULTS: Pulmonary betaAR density was similar in controls (12.4 +/- 1.7 pmol/g tissue), ARVC (11.6 +/- 1.7 pmol/g tissue, p = ns) and RVO-VT (12.8 +/- 2.0 pmol/g tissue, p = ns), whereas myocardial betaAR density was significantly reduced in ARVC (6.3 +/- 1.1 pmol/g tissue, p = 0.006) and RVO-VT (6.8 +/- 1.2 pmol/g tissue, p=0.02) as compared to controls (8.8+/-1.5 pmol/g tissue). CONCLUSION: The unchanged pulmonary betaAR density in the presence of a previously described significant reduction in myocardial betaAR density in the same patient principally supports our pathophysiological hypothesis that the myocardial betaAR density may be reduced in ARVC and RVO-VT because of an increase in local synaptic catecholamine levels due to an organ-limited presynaptic adrenergic dysfunction of the heart. Since in the present study only pulmonary betaAR density was measured, future functional studies excluding pulmonary betaAR desensitisation are required to finally prove the unchanged pulmonary sympathetic innervation in ARVC and RVO-VT.