Dosimetry during peptide receptor radionuclide therapy (PRRT) has mainly focused on normal organs and less on the tumors. The absorbed dose in one target tumor per patient and several response related factors were assessed in 23 pancreatic neuroendocrine neoplasms (P-NENs) and 25 small-intestinal NEN (SI-NENs) during PRRT with ¹⁷⁷Lu-DOTATATE. The total administered activity per patient was (mean ± standard error of mean (SEM) 31.8 ± 1.9 GBq for P-NENs and 36 ± 1.94 GBq for SI-NENs. The absorbed tumor dose was 143.5 ± 2 Gy in P-NENs, 168.2 ± 2 Gy in SI-NENs. For both NEN types, a dose-response relationship was found between the absorbed dose and tumor shrinkage, which was more pronounced in P-NENs. A significant drop in the absorbed dose per cycle was shown during the course of PRRT. Tumor vascularization was higher in P-NENs than in SI-NENs at baseline but equal post-PRRT. The time to progression (RECIST 1.1) was similar for patients with P-NEN (mean ± SEM 30 ± 1 months) and SI-NEN (33 ± 1 months). In conclusion, a dose response relationship was established for both P-NENs and SI-NENs and a significant drop in the absorbed dose per cycle was shown during the course of PRRT, which warrants further investigation to understand the factors impacting PRRT to improve personalized treatment protocol design.

Background: Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin receptors (SSTR) that can be targeted with somatostatin analogs (SSA). When activated with a single dose of SSA, the receptor-ligand complex is internalized, and the receptor is by default recycled within 24 h. Ongoing medication with long-acting SSAs at Ga-68-DOTA-SSA-PET has been shown to increase the tumor-to-normal organ contrast. This study was performed to investigate the time-dependent extended effect (7 h) of a single intravenous dose of 400 mu g short-acting octreotide on the tumor versus normal tissue uptake of Ga-68-DOTATOC.

Methods: Patients with small-intestinal NETs received a single intravenous dose of 400 mu g octreotide and underwent dynamic abdominal Ga-68-DOTATOC-PET/CT at three sessions (0, 3 and 6 h) plus static whole-body (WB) PET/CT (1, 4 and 7 h), starting each PET/CT session by administering 167 +/- 21 MBq, 23.5 +/- 4.2 mu g (mean +/- SD, n = 12) of Ga-68-DOTATOC. A previously acquired clinical whole-body Ga-68-DOTATOC scan was used as baseline. SUV and net uptake rate K-i were calculated in tumors, and SUV in healthy organs.

Results: Tumor SUV decreased significantly from baseline to 1 h post-injection but subsequently increased over time and became similar to baseline at 4 h and 7 h. The tumor net uptake rate, K-i, similarly increased significantly over time and showed a linear correlation both with SUV and tumor-to-blood ratio. By contrast, the uptake in liver, spleen and pancreas remained significantly below baseline levels also at 7 h and the receptor turn-over in tumors thus exceeded that in the normal tissue, with restitution of tumor Ga-68-DOTATOC uptake mainly completed at 7 h. These results however differed depending on tumor size, with significant increases in K-i and SUV between the 1st and 2nd PET, in large tumors (>= 4 mL) but not in small (> 1 to < 4 mL) tumors.

Conclusion: SSTR recycling is faster in small-intestinal NETs than in liver, spleen and pancreas. This opens the possibility to protect normal tissues during PRRT by administering a single dose of cold peptide hours before peptide receptor radionuclide therapy (PRRT), and most likely additionally improve the availability and uptake of the therapeutic preparation in the tumors.

Purpose

To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (¹⁸F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value).

Materials and Methods

An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated ¹⁸F-FDG tissue influx rate (K_i) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and K_i were studied in multiple tissues by using the Pearson correlation.

Results

Positive correlations were found between M value and K_i in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging–based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions.

Conclusion

This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated ¹⁸F-FDG influx rates, tissue depots, and M value.

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

OBJECTIVES

The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I. The purpose of this study was to evaluate different methods for producing [(11)C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations.

METHODS

Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations.

RESULTS

Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R(2)=0.99 for both BPND and R1; slopes 0.99 and 0.98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2.

CONCLUSION

The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [(11)C]PE2I PET studies.

The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [¹¹C]PE2I (n = 20) and [¹⁸F]FE-PE2I (n = 20) and the D2/3 tracer [¹¹C]raclopride (n = 18). Subjects with a [¹¹C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [¹¹C]DASB. Binding potential (BP_ND) and relative tracer delivery (R₁) values were calculated on regional and voxel-level. Striatal R₁ and BP_ND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BP_ND image. An inter-tracer comparison between [¹¹C]PE2I BP_ND and [¹¹C]DASB R₁ was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BP_ND and R₁ for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [¹¹C]PE2I BP_ND and [¹¹C]DASB R₁. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [¹¹ C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [¹¹ C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [¹¹ C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BP_ND ), with cerebellum as reference region, can be used to estimate [¹¹ C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BP_ND at the voxel level. As PET tracer, [¹¹ C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.

[F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration.

Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117.

METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed.

RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.

CONCLUSION: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision, and with a much lower white matter signal than seen with SUVr-1 images.

Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-C-11-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (C-11-Lu AE92686) and its tritiated analog H-3-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and C-11-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and C-11-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: C-11-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of C-11-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of C-11-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BP(ND)s were 6.5 +/- 0.3 (n = 3) and 7.5 +/- 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that C-11-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.

Background

We assessed the quantitative accuracy of cardiac perfusion measurements using dynamic contrast-enhanced MRI with simultaneous ¹⁵O-water PET as reference with a fully integrated PET-MR scanner.

Methods

15 patients underwent simultaneous DCE MRI and ¹⁵O-water PET scans at rest and adenosine-stress on an integrated PET-MR scanner. Correlation and agreement between MRI- and PET-based global and regional MBF values were assessed using correlation and Bland–Altman analysis.

Results

Three subjects were excluded due to technical problems. Global mean (± SD) MBF values at rest and stress were 0.97 ± 0.27 and 3.19 ± 0.70 mL/g/min for MRI and 1.02 ± 0.28 and 3.13 ± 1.16 mL/g/min for PET (P = 0.66 and P = 0.81). The correlations between global and regional MRI- and PET-based MBF values were strong (r = 0.86 and r = 0.75). The biases were negligible for both global and regional MBF comparisons (0.01 and 0.00 mL/min/g for both), but the limits of agreement were wide for both global and regional MBF, with larger variability for high MBF-values.

Conclusion

The correlation between simultaneous MBF measurements with DCE MRI and ¹⁵O-water PET measured in an integrated PET-MRI was strong but the agreement was only moderate indicating that MRI-based quantitative MBF measurements is not ready for clinical introduction.

BACKGROUND: (11)C-PIB PET is a promising non-invasive diagnostic tool for cardiac amyloidosis. Semiautomatic analysis of PET data is now available but it is not known how accurate these methods are for amyloid imaging. The aim of this study was to evaluate the feasibility of one semiautomatic software tool for analysis and visualization of (11)C-PIB left ventricular retention index (RI) in cardiac amyloidosis.

METHODS AND RESULTS: Patients with systemic amyloidosis and cardiac involvement (n = 10) and healthy controls (n = 5) were investigated with dynamic (11)C-PIB PET. Two observers analyzed the PET studies with semiautomatic software to calculate the left ventricular RI of (11)C-PIB and to create parametric images. The mean RI at 15-25 min from the semiautomatic analysis was compared with RI based on manual analysis and showed comparable values (0.056 vs 0.054 min(-1) for amyloidosis patients and 0.024 vs 0.025 min(-1) in healthy controls; P = .78) and the correlation was excellent (r = 0.98). Inter-reader reproducibility also was excellent (intraclass correlation coefficient, ICC > 0.98). Parametric polarmaps and histograms made visual separation of amyloidosis patients and healthy controls fast and simple.

CONCLUSION: Accurate semiautomatic analysis of cardiac (11)C-PIB RI in amyloidosis patients is feasible. Parametric polarmaps and histograms make visual interpretation fast and simple.

BACKGROUND: The use of integrated PET-MR offers new opportunities for comprehensive assessment of cardiac morphology and function. However, little is known on the quantitative accuracy of cardiac PET imaging with integrated time-of-flight PET-MR. The aim of the present work was to validate the GE Signa PET-MR scanner for quantitative cardiac PET perfusion imaging. Eleven patients (nine male; mean age 59 years; range 46-74 years) with known or suspected coronary artery disease underwent (15)O-water PET scans at rest and during adenosine-induced hyperaemia on a GE Discovery ST PET-CT and a GE Signa PET-MR scanner. PET-MR images were reconstructed using settings recommended by the manufacturer, including time-of-flight (TOF). Data were analysed semi-automatically using Cardiac VUer software, resulting in both parametric myocardial blood flow (MBF) images and segment-based MBF values. Correlation and agreement between PET-CT-based and PET-MR-based MBF values for all three coronary artery territories were assessed using regression analysis and intra-class correlation coefficients (ICC). In addition to the cardiac PET-MR reconstruction protocol as recommended by the manufacturer, comparisons were made using a PET-CT resolution-matched reconstruction protocol both without and with TOF to assess the effect of time-of-flight and reconstruction parameters on quantitative MBF values.

RESULTS: Stress MBF data from one patient was excluded due to movement during the PET-CT scanning. Mean MBF values at rest and stress were (0.92 ± 0.12) and (2.74 ± 1.37) mL/g/min for PET-CT and (0.90 ± 0.23) and (2.65 ± 1.15) mL/g/min for PET-MR (p = 0.33 and p = 0.74). ICC between PET-CT-based and PET-MR-based regional MBF was 0.98. Image quality was improved with PET-MR as compared to PET-CT. ICC between PET-MR-based regional MBF with and without TOF and using different filter and reconstruction settings was 1.00.

CONCLUSIONS: PET-MR-based MBF values correlated well with PET-CT-based MBF values and the parametric PET-MR images were excellent. TOF and reconstruction settings had little impact on MBF values.

BACKGROUND: The aim of the present study was to compare the quantitative flow responses of regadenoson against adenosine using cardiac ¹⁵O-water PET imaging in patients with suspected or known coronary artery disease (CAD).

METHODS: Hyperemic myocardial blood flow (MBF) after adenosine and regadenoson was compared using correlation and Bland-Altman analysis in 21 patients who underwent rest and adenosine ¹⁵O-water PET scans followed by rest and regadenoson ¹⁵O-water PET scans.

RESULTS: Global mean (± SD) MBF values at rest and stress were 0.92 ± 0.27 and 2.68 ± 0.80 mL·g·min for the adenosine study and 0.95 ± 0.29 and 2.76 ± 0.79 mL·g·min for the regadenoson study (P = 0.55 and P = 0.49). The correlations between global and regional adenosine- and regadenoson-based stress MBF were strong (r = 0.80 and r = 0.77). The biases were small for both global and regional MBF comparisons (0.08 and 0.09 mL·min·g), but the limits of agreement were wide for stress MBF.

CONCLUSION: The correlation between regadenoson- and adenosine-induced hyperemic MBF was strong but the agreement was only moderate indicating that established cut-off values for ¹⁵0-water PET should be used cautiously if using regadenoson as vasodilator.

BACKGROUND: The purpose of this work was to determine the optimal tracer kinetic model of (11)C-PIB and to validate the use of the simplified methods retention index (RI) and standardized uptake value (SUV) for quantification of cardiac (11)C-PIB uptake in amyloidosis. METHODS AND RESULTS: Single-tissue, reversible and irreversible two-tissue models were fitted to data from seven cardiac amyloidosis patients who underwent (11)C-PIB PET scans and arterial blood sampling for measurement of blood radioactivity and metabolites. The irreversible two-tissue model (2Tirr) best described cardiac (11)C-PIB uptake. RI and SUV showed high correlation with the rate of irreversible binding (Ki) from the 2Tirr model (r(2 )=0.95 and r(2 )=0.94). Retrospective data from 10 amyloidosis patients and 5 healthy controls were analyzed using RI, SUV, as well as compartment modelling with a population-average metabolite correction. All measures were higher in amyloidosis patients than in healthy controls (p=.001), but with an overlap between groups for Ki. CONCLUSION: An irreversible two-tissue model best describes the (11)C-PIB uptake in cardiac amyloidosis. RI and SUV correlate well with Ki from the 2Tirr model. RI and SUV discriminate better between amyloidosis patients and controls than Ki based on population-average metabolite correction.

Objectives: The study objective was to validate a recently introduced non-invasive image derived input function (IDIF) estimation method with the gold standard arterial blood sampling.

Methods: Six subjects (31-50 years old) were injected with 408±62 MBq of 15O-water simultaneously with the start of a 10 min PET scan on the SIGNA PET-MR (GE Healthcare, WI, Waukesha). During PET scanning, a sagittal vascular (inhance 3D velocity) MR series was used with the following parameters: TR=8.7 ms, TE=4.1 ms, FOV=24×21.6 cm, slice thickness=3 mm, 32 slices, velocity encoding=40, phase acceleration=2.0, and scan time=1:21 min. The PET list file was unlisted for every second and total true and scatter coincident events were plotted to identify tracer arrival into the brain arteries. Then, a short time frame over the arrival of the tracer to the cervical region was reconstructed to obtain a PET angiogram. The cervical arteries were then segmented using the MR vascular images and PETA images. Spill-over and spill- in artifacts were estimated using PETA images and the actual arterial volume was measured from the MR vascular images. The PET list file was unlisted and images were reconstructed for every 1 s for the first 30 s, every 3 s for the next 30 s, every 5 s for the 2nd minute, every 10 s for the 3rd and 4th minute and every 30 s for 5th to 10th minutes. The AIF was estimated by dividing total counts from the cervical arteries of each frame by the MR-based arterial volume. For each patient, blood samples were continuously drawn from the radial artery at the wrist using a peristaltic pump, and the tracer concentration in the arterial blood was measured using a Twilite two detector (Swisstrace) to estimate the AIF. In order to calculate the AIF at the brain arteries from these blood samples, the delay and dispersion of the arterial input function was corrected using standard PET-based methods. The CBF and distribution volume were calculated using both the IDIF method and the blood samples by minimizing the mean square of the error between the PET observations and model fit using the Nelder-Mead simplex algorithm in MATLAB (Mathworks, Wilmington, MA).

Results: Figure 1 shows the (a) PETA and (b) MR vascular images for one of the patients. The PETA images clearly show the arteries and the extent of the spill-over. Figure 2 compares the AIF curve estimated by the proposed IDIF method and the AIF curve measured by the blood samples. The comparison shows excellent correspondence between the IDIF method and the gold standard blood sampling method with 9% and 11% difference for the 1st pass and the entire AIF, respectively. The IDIF captures the AIF peak correctly and has increased signal-to-noise ratio compared to the blood sampling method. The delay and the dispersion of the AIF curve is nearly identical between the two methods. The CBF over the whole brain was measured 29.5±8.7 and 27.0±14 ml/s/100g with the AIF measured by IDIF method and blood samples, respectively with a mean difference of 14% between the two methods. The volume distribution over the whole brain was measured 0.5±0.1 for both methods with a mean difference of 15% between them.

Conclusion: As the results show, the proposed method is capable of determining a high fidelity IDIF from simultaneous PET/MRI data. Having a “blood-free” method that obviates the need for direct arterial sampling is of benefit to both investigators and their subjects, because of the high costs, inconvenience, and potential risks associated with arterial cannulation. It has applications beyond 15O-water PET, enabling pharmacokinetic modeling to be performed that is required for quantitative PET tracer studies. Research Support: GE Healthcare, Stanford University Lucas Center, Uppsala University.

Positron emission tomography (PET) is a radionuclide imaging technique that allows for noninvasive quantification of biochemical pathways in vivo. Utilizing positron emitting labelled compounds of interest, a myriad of biological processes can be visualized in the human heart. As such, PET has been proven invaluable to the noninvasive investigation of cardiovascular biology and physiology. Assessment of myocardial perfusion and substrate metabolism are of particular value in the evaluation of patients with (suspected) coronary artery disease (CAD) to detect ischemia and myocardial viability. This chapter will outline the fundamental principles of PET and technical considerations of cardiac PET imaging.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of 15O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.

Twenty-five subjects underwent two 10 min dynamic 15O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF.

The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using 15O-water PET and kinetic modelling.

Background

Respiratory motion during PET imaging reduces image quality. Data-driven gating (DDG) based on principal component analysis (PCA) can be used to identify respiratory signals. The use of DDG, without need for external devices, would greatly increase the feasibility of using respiratory gating in a routine clinical setting. The objective of this study was to evaluate data-driven gating in relation to external hardware gating and regular static image acquisition on PET-MRI data with respect to SUVmax and lesion volumes.

Methods

Sixteen patients with esophageal or gastroesophageal cancer (Siewert I and II) underwent a 6-min PET scan on a Signa PET-MRI system (GE Healthcare) 1.5-2 h after injection of 4 MBq/kg F-18-FDG. External hardware gating was done using a respiratory bellow device, and DDG was performed using MotionFree (GE Healthcare). The DDG raw data files and the external hardware-gating raw files were created on a Matlab-based toolbox from the whole 6-min scan LIST-file. For comparison, two 3-min static raw files were created for each patient. Images were reconstructed using TF-OSEM with resolution recovery with 2 iterations, 28 subsets, and 3-mm post filter. SUVmax and lesion volume were measured in all visible lesions, and noise level was measured in the liver. Paired t-test, linear regression, Pearson correlation, and Bland-Altman analysis were used to investigate difference, correlation, and agreement between the methods.

Results

A total number of 30 lesions were included in the study. No significant differences between DDG and external hardware-gating SUVmax or lesion volumes were found, but the noise level was significantly reduced in the DDG images. Both DDG and external hardware gating demonstrated significantly higher SUVmax (9.4% for DDG, 10.3% for external hardware gating) and smaller lesion volume (- 5.4% for DDG, - 6.6% for external gating) in comparison with non-gated static images.

Conclusions

Data-driven gating with MotionFree for PET-MRI performed similar to external device gating for esophageal lesions with respect to SUVmax and lesion volume. Both gating methods significantly increased the SUVmax and reduced the lesion volume in comparison with non-gated static acquisition. DDG resulted in reduced image noise compared to external device gating and static images.

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single positron emission tomography study can provide both functional and molecular information.

METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change.

RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317.

DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

Objectives: The penalized likelihood estimation reconstruction algorithm Q.Clear (GE Healthcare) allows for full convergence and edge preservation through a block sequential regularized expectation maximization technique. In this study the performance of Q.Clear was investigated for different penalization factors (β) with the aim to optimize its clinical use for four different tracers.

Methods: Q.Clear reconstructions with β values of 200, 400, 600 and 800 were compared to time-of-flight ordered subset expectation maximization (TF-OSEM) (3 iterations, 16 subsets and 5 mm Gaussian filter) with point spread function recovery. Clinical whole-body PET/CT (Discovery MI, GE Healthcare) scans with ⁶⁸Ga-DOTATOC, ¹⁸F-FDG, ¹¹C-acetate or ¹⁸F-fluoride were analyzed for level of noise in healthy liver tissue, signal to noise ratio (SNR), signal to background ratio (SBR) and maximum standardized uptake value (SUV_max). In addition, acquisition times per bed position and transaxial field of view (FOV) of the reconstructed images were varied. For each tracer, images from 10 patients were included, with a mean of 30 lesions per tracer. A spherical reference volume of interest (VOI) was placed in the liver and lesions were delineated employing a 41% threshold of the maximum voxel.

Results: The lowest levels of noise were reached with the highest beta factor resulting in the highest SNR, but this in turn gave the lowest SBR. Noise equivalence to OSEM was found with β 600 for ⁶⁸Ga-DOTATOC, ¹⁸F-FDG and ¹⁸F-fluoride, and β 400 for ¹¹C-acetate with a resulting significant increase of SUV_max (19.4%, 9.7%, 22.5% and 19.0% respectively) (P < 0.0001, paired t-test), SNR (22.1%, 22.6%, 9.5% and 33.6%) and SBR (19.5%, 11.7%, 21.3% and 18.5%) compared to OSEM. SNR decreased while SBR increased for all tracers when extending FOV from 500 to 700 mm, but only significantly for ¹⁸F-fluoride. Decreasing image acquisition time gave no statistical difference of SUV_max for ⁶⁸Ga-DOTATOC, ¹⁸F-fluoride (2 to 1.5 min) for any reconstruction method nor for ¹¹C-acetate (3 to 2 min) with β 蠅 400. Decreasing time for ¹⁸F-FDG (3 to 2 min) resulted in a change of optimal beta to β 800 in order to reach noise equivalence to OSEM along with maintaining a higher SNR than OSEM.

Conclusion: Images reconstructed by Q.Clear result in a tracer-dependent increase in tumour SUV_max values compared to OSEM at matched levels of noise, and an improved SNR. The optimal penalization factor, both in terms of noise-equivalence to OSEM and in terms of absolute SNR, is tracer dependent.

BACKGROUND: Block-sequential regularized expectation maximization (BSREM) is a fully convergent iterative image reconstruction algorithm. We hypothesize that tracers with different distribution patterns will result in different optimal settings for the BSREM algorithm. The aim of this study was to evaluate the image quality with variations in the applied β-value and acquisition time for three positron emission tomography (PET) tracers. NEMA image quality phantom measurements and clinical whole-body digital time-of-flight (TOF) PET/computed tomography (CT) examinations with ⁶⁸Ga-DOTATOC (n = 13), ¹⁸F-fluoride (n = 10), and ¹¹C-acetate (n = 13) were included. Each scan was reconstructed using BSREM with β-values of 133, 267, 400, and 533, and ordered subsets expectation maximization (OSEM; 3 iterations, 16 subsets, and 5-mm Gaussian post-processing filter). Both reconstruction methods included TOF and point spread function (PSF) recovery. Quantitative measures of noise, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) were analysed for various acquisition times per bed position (bp).

RESULTS: The highest β-value resulted in the lowest level of noise, which in turn resulted in the highest SNR and lowest SBR. Noise levels equal to or lower than those of OSEM were found with β-values equal to or higher than 400, 533, and 267 for ⁶⁸Ga-DOTATOC, ¹⁸F-fluoride, and ¹¹C-acetate, respectively. The specified β-ranges resulted in increased SNR at a minimum of 25% (P < 0.0001) and SBR at a maximum of 23% (P < 0.0001) as compared to OSEM. At a reduced acquisition time by 25% for ⁶⁸Ga-DOTATOC and ¹⁸F-fluoride, and 67% for ¹¹C-acetate, BSREM with β-values equal to or higher than 533 resulted in noise equal to or lower than that of OSEM at full acquisition duration (2 min/bp for ⁶⁸Ga-DOTATOC and ¹⁸F-fluoride, 3 min/bp for ¹¹C-acetate). The reduced acquisition time with β 533 resulted in increased SNR (16-26%, P < 0.003) and SBR (6-18%, P < 0.0001 (P = 0.07 for ¹¹C-acetate)) compared to the full acquisition OSEM.

CONCLUSIONS: Within tracer-specific ranges of β-values, BSREM reconstruction resulted in increased SNR and SBR with respect to conventional OSEM reconstruction. Similar SNR, SBR, and noise levels could be attained with BSREM at relatively shorter acquisition times or, alternatively, lower administered dosages, compared to those attained with OSEM.

PURPOSE: To assess how some of the new developments in brain positron emission tomography (PET) image reconstruction affect quantitative measures and software-aided assessment of pathology in patients with neurodegenerative diseases.

METHODS: PET data were grouped into four cohorts: prodromal Alzheimer's disease patients and controls receiving [¹⁸F]flutemetamol, and neurodegenerative disease patients and controls receiving [¹⁸F]FDG PET scans. Reconstructed images were obtained by ordered-subsets expectation maximization (OSEM; 3 iterations (i), 16/34 subsets (s), 3/5-mm filter, ±time-of-flight (TOF), ±point-spread function (PSF)) and block-sequential regularized expectation maximization (BSREM; TOF, PSF, β-value 75-300). Standardized uptake value ratios (SUVR) and z-scores were calculated (CortexID Suite, GE Healthcare) using cerebellar gray matter, pons, whole cerebellum and whole brain as reference regions.

RESULTS: In controls, comparable results to the normal database were obtained with OSEM 3i/16 s 5-mm reconstruction. TOF, PSF and BSREM either increased or decreased the relative uptake difference to the normal subjects' database within the software, depending on the tracer and chosen reference area, i.e. resulting in increased absolute z-scores. Normalizing to pons and whole brain for [¹⁸F]flutemetamol and [¹⁸F]FDG, respectively, increased absolute differences between reconstructions methods compared to normalizing to cerebellar gray matter and whole cerebellum when applying TOF, PSF and BSREM.

CONCLUSIONS: Software-aided assessment of patient pathologies should be used with caution when employing other image reconstruction methods than those used for acquisition of the normal database.

The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor β were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and β-factors of 133, 267, 400, and 533—and using TOF OSEM with point-spread function—for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest β-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A β-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a β-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a β-factor of 400 obtained the highest mean whereas a β-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.

Accurate localization of recurrent prostate cancer (PCa) is critical, especially if curative therapy is intended. With the aim to optimize target-to-background uptake ratio in Ga-68-PSMA-11 PET, we investigated the image quality and quantitative measures of regularized reconstruction by block-sequential regularized expectation maximization (BSREM).

Methods:

The study encompassed retrospective reconstruction and analysis of 20 digital time-of-flight (TOF) PET/CT examinations acquired 60 min post injection of 2 MBq/kg of Ga-68-PSMA-11 in PCa patients with biochemical relapse after primary treatment. Reconstruction by ordered-subsets expectation maximization (OSEM; 3 iterations, 16 subsets, 5 mm gaussian postprocessing filter) and BSREM (beta-values of 100-1600) were used, both including TOF and point spread function (PSF) recovery. Background variability (BV) was measured by placing a spherical volume of interest in the right liver lobe and defined as the standard deviation divided by the mean standardized uptake value (SUV). The image quality was evaluated in terms of signal-to-noise ratio (SNR) and signal-to-background ratio (SBR), using SUVmax of the lesions. A visual assessment was performed by four observers.

Results:

OSEM reconstruction produced images with a BV of 15%, whereas BSREM with a beta-value above 300 resulted in lower BVs than OSEM (36% with beta 100, 8% with beta 1300). Decreasing the acquisition duration from 2 to 1 and 0.5 min per bed position increased BV for both reconstruction methods, although BSREM with beta-values equal to or higher than 800 and 1200, respectively, kept the BV below 15%. In comparison of BSREM with OSEM, the mean SNR improved by 25 to 66% with an increasing beta-value in the range of 200-1300, whereas the mean SBR decreased with an increasing beta-value, ranging from 0 to 125% with a beta-value of 100 and 900, respectively. Decreased acquisition duration resulted in beta-values of 800 to 1000 and 1200 to 1400 for 1 and 0.5 min per bed position, respectively, producing improved image quality measures compared with OSEM at a full acquisition duration of 2 min per bed position. The observer study showed a slight overall preference for BSREM beta 900 although the interobserver variability was high.

Conclusion:

BSREM image reconstruction with beta-values in the range of 400-900 resulted in lower BV and similar or improved SNR and SBR in comparison with OSEM.

P-glycoprotein function is associated with a number of neurodegenerative and psychiatric diseases as well as with pharmacoresistance to for example antiepileptic drugs. The ability to measure P-gp function in vivo would allow for an increased understanding of the mechanisms of disease and treatment. This review assesses the various approaches to in vivo quantification of P-gp function using currently available P-gp tracers and PET in humans. First, the use of compartment models, and their interpretation in terms of P-gp function at the blood-brain barrier, is discussed. Then, the methods that have been used to quantify PET data of the P-gp tracers [11C]verapamil, [11C]N-desmetyl-loperamide (dLop), [11C]laniquidar, [11C]phenytoin, [11C]tariquidar and [11C]elacridar are reviewed. In summary, the extraction of P-gp substrate PET tracers, which is their plasma to tissue rate constant K1 corrected for variations in regional cerebral blood flow, is generally considered to be the preferred measure of P-gp function.

The use of positron emission tomography (PET) has so far mainly been limited to a few nuclides with short half-lives such as ¹¹C and ¹⁸F. Certain applications require nuclides with longer half-lives, such as ⁷⁶Br and ⁵²Fe. In radionuclide therapy positron emitting analogues of therapeutic nuclides, such as ^110mIn, or daughter nuclides, such as ¹³⁴La, can enable improved dosimetry with the use of PET. A challenge associated with the use of these positron emitters is that they emit gamma radiation in cascade with positrons, which complicates quantitative PET imaging. Other possible problems are the high energies of the emitted positrons, and the decay of ⁵²Fe to the short-lived positron emitter ^52mMn.

Performance measurements were made to investigate the effects of these decay characteristics on the quantitative accuracy, spatial resolution, and other parameters of PET. The distribution of gamma radiation coincidences in PET data was studied and correction methods were implemented and evaluated. PET resolution degrades with 1-2 mm for the studied nuclides in comparison with ¹⁸F. The implemented sinogram tail fit and delayed coincidence based gamma radiation coincidence correction methods lead to a quantitative accuracy similar as for ¹⁸F and to improved image contrast. Standard dead time corrections are not adequate for gamma-emitting nuclides. Noise equivalent count rates are considerably lower for ⁷⁶Br than for ¹⁸F at clinically relevant radioactivity concentrations.

A method to correct ⁵²Fe patient data for the contribution of ^52mMn is discussed. The use of ^110mIn is evaluated in a patient study and compared to SPECT imaging with ¹¹¹In. A dosimetric and PET evaluation of the use of ¹³⁴Ce/¹³⁴La for radionuclide therapy and dosimetry is presented. Dosimetry of ⁷⁶Br-labelled antibodies is studied in a pig model. Finally, the possibility to use PET for dosimetry during radionuclide therapy is studied and a nonuniform dose calculation program is presented.

Objectives: Quantitative imaging of the synaptic vesicle glycoprotein 2A (SV2A) with PET can be used as a measure of synaptic density in the human brain (Finnema et al, Science Tr Med 2016), changes of which occur in many neurodegenerative diseases. ¹¹C-UCBA has previously been validated as an SV2A tracer in pigs (Estrada et al, Nucl Med Biol 2016), showing dose-dependent blocking and reversible binding. The aim of the present work was to evaluate tracer kinetic models and simplified methods for quantification of synaptic density using ¹¹C-UCBA in humans.

Methods: Eight subjects (6 epilepsy patients, 2 controls) underwent 90 min PET scans starting with injection of 5 MBq/kg ¹¹C-UCBA on a time-of-flight integrated PET-MR scanner (Signa PET-MR, GE Healthcare). Arterial blood was withdrawn for measurements of whole blood and plasma concentrations and metabolite analysis. Images were reconstructed using zero-echo-time MR-based attenuation correction, accounting for bone attenuation. A probabilistic VOI template was defined on a T1-MRI image, acquired during the PET scan, and transferred to the dynamic PET images. A centrum semiovale VOI was drawn as potential reference tissue. Data were analysed using single-tissue (1T2k), two-tissue irreversible (2T3k) and reversible (2T4k) models, as well as the simplified reference tissue model (SRTM) and plasma- and reference-Logan methods, resulting in total distribution volume (V_T) and binding potential (BP_ND) values, with binding potential both estimated directly and as distribution volume ratio to centrum semiovale (DVR). The optimal compartment model was determined using the Akaike information criterion (AIC). Standardized uptake value ratios (SUVR) at various time points were compared to modelling outcomes using regression analysis.

Results: Plasma and brain kinetics of ¹¹C-UCBA were slow, with peak activity in brain at 70-80 min. Parent fraction was approximately 50% at 90 min. Plasma-input data were best described using the 2T4k model, but this could often not provide robust V_T or BP_ND values. Mean plasma-Logan V_T was 24±17. Plasma-Logan DVR using centrum semiovale as reference tissue correlated well with 2T4k DVR (R² 0.94) for those regions where robust DVR values could be determined. Reference-Logan DVR showed good correlation with plasma-Logan DVR (R² 0.72). Plasma-Logan DVR-1 and SUVR-1 images are shown in Figure 1. SUVR for the 40-60 and 70-90 min intervals correlated well with reference-Logan DVR (R² 0.92 and 0.98).

Conclusion: Slow kinetics of ¹¹C-UCBA resulted in poor robustness of outcome parameters of reversible compartment models. However, reference-Logan DVR correlated well with plasma-Logan DVR. SUVR at 70-90 min p.i. correlated well with DVR and may be used as a simplified measure of synaptic density using ¹¹C-UCBA. Research Support: Uppsala County Council

Purpose:

Positron emission tomography using 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [¹⁸F]FLT in locally advanced breast cancer (LABC).

Procedures:

Fifteen LABC patients underwent dynamic [¹⁸F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [¹⁸F]FLT, K _i , determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [¹⁸F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.

Results:

No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.

Conclusions:

In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [¹⁸F]FLT.

[¹¹C]5-Hydroxy-tryptophan ([¹¹C]5-HTP) is a Positron Emission Tomography marker for serotonergic biosynthesis and degradation, with use in imaging of neuroendocrine tumors and recently also the endocrine pancreas in diabetes. In order to further develop [¹¹C]5-HTP as a quantitative in vivo tool for understanding the mechanisms of serotonin signaling in human pancreas, we aimed to develop a kinetic modeling approach sensitive for changes in serotonin biosynthesis, retention and degradation. Cynomolgus monkeys were examined by [¹¹C]5-HTP PET/CT, either at baseline (n=9) or following intravenous pretreatment with 3 mg/kg carbidopa (Dopa Decarboxylase inhibitor, n=3) or 2 mg/kg clorgyline (Monoamine Oxidase-A inhibitor, n=5). The dynamic tissue uptake was analysed by a 2-tissue compartment model including an efflux mechanism from the second tissue compartment (2TC k_loss), which theoretically reproduces the known processing of 5-HTP in neuroendocrine cells. The 2TC k_loss model could accurately describe all three modes of tissue kinetics depending on the pretreatment regiment. Rate constant k₃ (corresponding to DDC activity) and the macro-parameter Flux (K_i) was decreased (P<0.05) by carbidopa pretreatment, while k₂ (corresponding to cellular washout of intact [¹¹C]5-HTP) was increased (P<0.05). The efflux parameter k_loss (corresponding to MAO-A activity) was decreased (P<0.05) by pretreatment of clorgyline, while the macro-parameter Flux/Efflux ratio (K_i/k_loss) was increased (P<0.0001). We present a compartment model analysis method that can quantitatively assess in vivo pharmacological interactions with several of the key enzymatic steps of the serotonergic biosynthesis in pancreas.

High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using O-15-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients. Methods: Nine patients with documented progressive disease despite all established therapy underwent O-15-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model. Results: Imatinib administration during 6-7 d increased PTF from 0.62 +/- 0.12 to 0.69 +/- 0.13, compared with baseline and day 2 (P = 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively. Conclusion: Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. O-15-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.