Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

PURPOSE: [18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. METHODS: In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. RESULTS: AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. CONCLUSION: Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

Interobserver variability in interim PET assessment in Hodgkin lymphoma-reasons and solutions.

INTRODUCTION: Interim PET (iPET) assessment is important for response adaptation in Hodgkin lymphoma (HL). The current standard for iPET assessment is the Deauville score (DS). The aim of our study was to evaluate the causes of interobserver variability in assigning the DS for iPET in HL patients and to make suggestions for improvement. METHODS: All evaluable iPET scans from the RAPID study were re-read by two nuclear physicians, blinded to the results and patient outcomes in the RAPID trial. The iPET scans were assessed visually according to the DS and, thereafter, quantified using the qPET method. All discrepancies of more than one DS level were re-evaluated by both readers to find the reason for the discordant result. RESULTS: In 249/441 iPET scans (56%) a concordant visual DS result was achieved. A "minor discrepancy" of one DS level occurred in 144 scans (33%) and a "major discrepancy" of more than one DS level in 48 scans (11%). The main causes for major discrepancies were 1) different interpretation of PET-positive lymph nodes-malignant vs. inflammatory; 2) lesions missed by one reader and 3) different assessment of lesions in activated brown fat tissue. In 51% of the minor discrepancy scans with residual lymphoma uptake, additional quantification resulted in a concordant quantitative DS result. CONCLUSION: Discordant visual DS assessment occurred in 44% of all iPET scans. The main reason for major discrepancies was the different interpretation of PET positive lymph nodes as malignant or inflammatory. Disagreements in evaluation of the hottest residual lymphoma lesion can be solved by the use of semi-quantitative assessment.

Assessment of perfusion deficit with early phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol-amyloid-PET recordings.

PURPOSE: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease. METHODS: We obtained early-phase PET recordings with [18F]PI-2620 (0.5-2.5 min p.i.) and [18F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to ß-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests. RESULTS: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90). CONCLUSION: The early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [ 18 F]PI-2620.

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = -0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

Quantitative assessment of interim PET in Hodgkin lymphoma: An evaluation of the qPET method in adult patients in the RAPID trial.

AIM: qPET is a quantitative method used to assess FDG-PET response in lymphoma. qPET was developed using 898 scans from children with Hodgkin Lymphoma (HL) in the EuroNet-PHL-C1 (C1) trial. The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial. METHODS: PET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1-5 in C1 were used to derive quantitative DS (qDS) for RAPID patients. RESULTS: PET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal 'normal' distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response (CMR; DS 1-3) vs. no-CMR using the Lugano classification. CONCLUSION: qPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial.

Clinical Use and Utility of Amyloid Imaging.

Currently, 3 amyloid PET tracers are approved and commercially available for clinical use. They allow for the accurate in vivo detection of amyloid plaques, one hallmark of Alzheimer disease. Here, we review the current knowledge on the clinical use and utility of amyloid imaging. Appropriate use criteria for the clinical application of amyloid imaging are established, and most currently available data point to their validity. Visual amyloid image analysis is highly standardized. Disclosure of amyloid imaging results is desired by many cognitively impaired subjects and seems to be safe once appropriate education is delivered to the disclosing clinicians. Regarding clinical utility, increasing evidence points to a change in diagnosis via amyloid imaging in about 30% of cases, to an increase in diagnostic confidence in about 60% of cases, to a change in patient management in about 60% of cases, and specifically to a change in medication in about 40% of cases. Also, amyloid imaging results seem to have a relevant impact on caregivers. Further, initial simulation studies point to a potential positive effect on patient outcome and to cost effectiveness of amyloid imaging. These features, however, will require confirmation in prospective clinical trials. More work is also required to determine the clinical utility of amyloid imaging specifically in subjects with mild cognitive impairment and in comparison with or in conjunction with other Alzheimer disease biomarkers. In summary, the clinical use of amyloid imaging is being studied, and the currently available data point to a relevant clinical utility of this imaging technique. Ongoing research will determine whether this accurate and noninvasive approach to amyloid plaque load detection will translate into a benefit to cognitively impaired subjects.

Optimized classification of 18F-Florbetaben PET scans as positive and negative using an SUVR quantitative approach and comparison to visual assessment.

INTRODUCTION: Standardized uptake value ratios (SUVRs) calculated from cerebral cortical areas can be used to categorize 18F-Florbetaben (FBB) PET scans by applying appropriate cutoffs. The objective of this work was first to generate FBB SUVR cutoffs using visual assessment (VA) as standard of truth (SoT) for a number of reference regions (RR) (cerebellar gray matter (GCER), whole cerebellum (WCER), pons (PONS), and subcortical white matter (SWM)). Secondly, to validate the FBB PET scan categorization performed by SUVR cutoffs against the categorization made by post-mortem histopathological confirmation of the Aß presence. Finally, to evaluate the added value of SUVR cutoff categorization to VA. METHODS: SUVR cutoffs were generated for each RR using FBB scans from 143 subjects who were visually assessed by 3 readers. SUVR cutoffs were validated in 78 end-of life subjects using VA from 8 independent blinded readers (3 expert readers and 5 non-expert readers) and histopathological confirmation of the presence of neuritic beta-amyloid plaques as SoT. Finally, the number of correctly or incorrectly classified scans according to pathology results using VA and SUVR cutoffs was compared. RESULTS: Composite SUVR cutoffs generated were 1.43 (GCER), 0.96 (WCER), 0.78 (PONS) and 0.71 (SWM). Accuracy values were high and consistent across RR (range 83-94% for histopathology, and 85-94% for VA). SUVR cutoff performed similarly as VA but did not improve VA classification of FBB scans read either by expert readers or the majority read but provided higher accuracy than some non-expert readers. CONCLUSION: The accurate scan classification obtained in this study supports the use of VA as SoT to generate site-specific SUVR cutoffs. For an elderly end of life population, VA and SUVR cutoff categorization perform similarly in classifying FBB scans as Aß-positive or Aß-negative. These results emphasize the additional contribution that SUVR cutoff classification may have compared with VA performed by non-expert readers.

Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.

PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study.

UNLABELLED: Training for accurate image interpretation is essential for the clinical use of ß-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). METHODS: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for ß-amyloid plaques. RESULTS: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person-trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person-trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person-trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person-trained interpreters and in 87.7% of scans for e-trained interpreters. CONCLUSION: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.

Internal dose assessment of (-)-18F-flubatine, comparing animal model datasets of mice and piglets with first-in-human results.

UNLABELLED: (-)-(18)F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype α4ß2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers. METHODS: Twenty-seven female CD1 mice (weight ± SD, 28.2 ± 2.1 g) received intravenous injection of 0.75 ± 0.33 MBq of (-)-(18)F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a γ counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age ± SD, 44 ± 3 d; weight ± SD, 13.7 ± 1.7 kg) and 3 humans (2 men and 1 woman; age ± SD, 59.6 ± 3.9 y; weight ± SD, 74.3 ± 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 ± 7.4 and 353.7 ± 10.2 MBq of (-)-(18)F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time-activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103. RESULTS: After the injection of (-)-(18)F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (-)-(18)F-flubatine was estimated to be 12.5 µSv/MBq in mice, 14.7 ± 0.7 µSv/MBq in piglets, and 23.4 ± 0.4 µSv/MBq in humans. CONCLUSION: As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (-)-(18)F-flubatine by 34%-44%.

Assessment of α7 nicotinic acetylcholine receptor availability in juvenile pig brain with [¹8F]NS10743.

PURPOSE: To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [(18)F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). METHODS: Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [(18)F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg(-1) bolus + 1 mg·kg(-1)·h(-1) continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. RESULTS: Plasma [(18)F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV(max) was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV(max) 1.53 ± 0.32). Administration of NS6740 significantly decreased [(18)F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP(ND). The baseline BP(ND) ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP(ND) in regions with high [(18)F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP(ND) in low binding regions (cerebellum: -16%, p = 0.2). CONCLUSION: This study confirms the potential of [(18)F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.

Changes in myocardial perfusion due to physical exercise in patients with stable coronary artery disease.

PURPOSE: Percutaneous transluminal coronary angioplasty (PTCA) is one of the main therapy options for patients with coronary artery disease (CAD), resulting in an improvement in myocardial perfusion and exercise capacity. Nevertheless, studies have also demonstrated a positive effect of regular exercise training on myocardial perfusion and maximum exercise capacity. The aim of this study was to evaluate changes in myocardial stress perfusion after 1 year of exercise training in comparison with the effects of PTCA in patients with CAD. METHODS: In 66 male patients with angiographically confirmed significant coronary artery stenosis in one target vessel, myocardial perfusion scintigraphy was performed at baseline and 12 months after randomisation into either a physical exercise group or a PTCA group. Circumferential count rate profiles in 16 wall segments were classified according to their relative count rate and localisation within or outside the area supplied by the stenosed vessel. RESULTS: Ischaemic segments showed a significant improvement in myocardial count rate within the target area after 12 months in both the PTCA and the training group (PTCA group: from 76.8+/-4.9% to 86.6+/-10.9%, p=0.03; training group: from 74.0+/-7.3% to 83.7+/-10.8%, p<0.01). Outside the target area only the training group showed a significant improvement (from 77.7+/-4.4% to 91.7+/-4.8%, p<0.01). CONCLUSION: Our data indicate a significant improvement in stress myocardial perfusion in the training group after 12 months. The ischaemia is reduced not only in the target region of the leading stenosis but also in other ischaemic myocardial areas. In contrast, after PTCA stress perfusion improves only in the initially ischaemic parts of the target area.

Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial.

BACKGROUND: Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization). METHODS AND RESULTS: A total of 101 male patients aged < or =70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher event-free survival (88% versus 70% in the PCI group, P=0.023) and increased maximal oxygen uptake (+16%, from 22.7+/-0.7 to 26.2+/-0.8 mL O2/kg, P<0.001 versus baseline, P<0.001 versus PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, 6956 dollars was spent in the PCI group versus 3429 dollars in the training group (P<0.001). CONCLUSIONS: Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.