[ 68 Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [ 68 Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [ 177 Lu]Lu-PSMA-617, [ 225 Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [ 68 Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68 Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [ 68 Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68 Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [ 68 Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04–1.57 GBq (28–42 mCi); cyclotron method (single target), 1.47–1.89 GBq (40–51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68 Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [ 68 Ga]Ga-PSMA-11 prepared using the two production methods.

Purpose To optimize the direct production of 68 Ga on a cyclotron, via the 68 Zn(p,n) 68 Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68 Ga, extraction of [ 68 Ga]GaCl 3 and subsequent [ 68 Ga]Ga-PSMA-11 labeling using an automated synthesis module. Methods Irradiations of a 1.0 M solution of [ 68 Zn]Zn(NO 3 ) 2 in dilute (0.2–0.3 M) HNO 3 were conducted using GE PETtrace cyclotrons and GE 68 Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67 Ga through the 68 Zn(p,2n) 67 Ga reaction without unduly compromising 68 Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude 68 Ga production was measured. The extraction of [ 68 Ga]GaCl 3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [ 68 Ga]GaCl 3 was used to label [ 68 Ga]Ga-PSMA-11 that was intended for clinical use. Results The decay corrected yield of 68 Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [ 68 Zn]Zn(NO 3 ) 2 at 0.3 M HNO 3. Target/chemistry performance was more consistent when compared with 0.2 M HNO 3 . Radionuclidic purity of 68 Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined 66/67 Ga) for a practical clinical product shelf-life. The activity yield of [ 68 Ga]GaCl 3 was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [ 68 Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [ 68 Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). Conclusion Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [ 68 Ga]Ga-PSMA-11 and is a viable alternative to traditional 68 Ge/ 68 Ga generators.

Purpose : To optimize the direct production of 68 Ga on a cyclotron, via the 68 Zn(p,n) 68 Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68 Ga, extraction of [ 68 Ga]GaCl 3 and subsequent [ 68 Ga]Ga-PSMA-11 labeling using an automated synthesis module. Methods : Irradiations of a 1.0 M solution of [ 68 Zn]Zn(NO 3 ) 2 in dilute (0.2-0.3 M) HNO 3 were conducted using GE PETtrace cyclotrons and GE 68 Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67 Ga through the 68 Zn(p,2n) 67 Ga reaction without unduly compromising 68 Ga yields. We also evaluated the effects of varying beam times (50-75 min) and beam currents (27-40 μA). Crude 68 Ga production was measured. The extraction of [ 68 Ga]GaCl 3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [ 68 Ga]GaCl 3 was used to label [ 68 Ga]Ga-PSMA-11 that was intended for clinical use. Results : The decay corrected yield of 68 Ga at EOB was typically >3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [ 68 Zn]Zn(NO 3 ) 2 at 0.3 M HNO 3. Target/chemistry performance was more consistent when compared with 0.2 M HNO 3 . Radionuclidic purity of 68 Ga was typically >99.8% at EOB and met the requirements specified in the European Pharmacopoeia (<2% combined 66/67 Ga) for a practical clinical product shelf-life. The activity yield of [ 68 Ga]GaCl 3 was typically >50% (~1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [ 68 Ga]Ga-PSMA-11 were near quantitative (~1.67 GBq, 45mCi) at EOS. Cyclotron produced [ 68 Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing , and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). Conclusion: Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [ 68 Ga]Ga-PSMA-11 and is a viable alternative to traditional 68 Ge/ 68 Ga generators.

This chapter briefly introduces medical imaging, kinetic modeling technique, and parametric images in molecular imaging. It then explains major parametric estimation methods such as standardized uptake value, graphical analysis, and linear least squares methods. It further describes noninvasive methods including image-derived, reference tissue model, population-based input functions, and cascaded modeling approaches. It finally presents clinical applications of parametric images in blood flow, oxygen consumption, glucose metabolism, and receptor-specific binding.

Exercise improves mucus clearance in people without lung disease and those with chronic bronchitis. No study has investigated exercise alone for mucus clearance in cystic fibrosis (CF). The aim of this study was to compare the effects of treadmill exercise to resting breathing and airway clearance with positive expiratory pressure (PEP) therapy on mucus clearance in adults with CF. This 3-day randomised, controlled, crossover trial included 14 adults with mild to severe CF lung disease (forced expiratory volume in 1 s % predicted 31-113%). Interventions were 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption or PEP therapy (including huffing and coughing). Mucus clearance was measured using the radioaerosol technique and gamma camera imaging. Treadmill exercise improved whole lung mucus clearance compared to resting breathing (mean difference 3%, 95% CI 2-4); however, exercise alone was less effective than PEP therapy (mean difference -7%, 95% CI -6- -8). When comparing treadmill exercise to PEP therapy, there were no significant differences in mucus clearance from the intermediate and peripheral lung regions, but significantly less clearance from the central lung region (likely reflecting the huffing and coughing that was only in PEP therapy). It is recommended that huffing and coughing are included to maximise mucus clearance with exercise.

In people with and without Cystic Fibrosis (CF), does side lying during nebulisation change: the proportion of the dose loaded in the nebuliser that is deposited in the lungs; the uniformity of deposition throughout the lungs; or the apical drug density as a percentage of the drug density in the remaining lung? Do these effects differ depending on the degree of lung disease present? A randomised crossover trial with concealed allocation, intention-to-treat analysis and blinded assessors, involving 39 adults: 13 healthy, 13 with mild CF lung disease (FEV1 > 80%pred), and 13 with more advanced CF lung disease (FEV1 < 80%pred). In random order, 4 mL of nebulised radioaerosol was inhaled in upright sitting and in alternate right and left side lying at 2-min intervals, for 20 min. Compared to sitting upright, lung deposition and the uniformity of deposition were not significantly altered by side lying in any of the three groups. In sitting, the density of the deposition was significantly less in the apical regions than in the rest of the lung in all participants. Side lying significantly improved apical deposition in healthy adults (MD, 13%; 95% CI, 7 to 19), and in minimal CF lung disease (MD, 4%; 95% CI, 1 to 7) but not in advanced disease (MD, 4%; 95% CI, − 2 to 9). Alternating between right and left side lying during nebulisation significantly improves apical deposition in healthy adults and in adults with mild CF lung disease, without substantial detriment to overall deposition. ACTRN12611000674932 (Healthy), ACTRN12611000672954 (CF) Retrospectively registered 4/7/2011.

BACKGROUND AND OBJECTIVE:It can be challenging to delineate the target object in anatomical imaging when the object boundaries are difficult to discern due to the low contrast or overlapping intensity distributions from adjacent tissues.METHODS:We propose a topo-graph model to address this issue. The first step is to extract a topographic representation that reflects multiple levels of topographic information in an input image. We then define two types of node connections - nesting branches (NBs) and geodesic edges (GEs). NBs connect nodes corresponding to initial topographic regions and GEs link the nodes at a detailed level. The weights for NBs are defined to measure the similarity of regional appearance, and weights for GEs are defined with geodesic and local constraints. NBs contribute to the separation of topographic regions and the GEs assist the delineation of uncertain boundaries. Final segmentation is achieved by calculating the relevance of the unlabeled nodes to the labels by the optimization of a graph-based energy function. We test our model on 47 low contrast CT studies of patients with non-small cell lung cancer (NSCLC), 10 contrast-enhanced CT liver cases and 50 breast and abdominal ultrasound images. The validation criteria are the Dice's similarity coefficient and the Hausdorff distance.RESULTS:Student's t-test show that our model outperformed the graph models with pixel-only, pixel and regional, neighboring and radial connections (p-values <0.05).CONCLUSIONS:Our findings show that the topographic representation and topo-graph model provides improved delineation and separation of objects from adjacent tissues compared to the tested models.

670 Objectives: Our aim was to optimise a one-step radiosynthesis of [18F]PSMA-1007 on a GE FASTlab 2 radiochemistry module using disposable cassettes. Methods: We optimised the 18F-nucleophilic substitution reactions on the trimethyl ammonium pyridinium trifluoroacetate and acetate derivatives of the unprotected PSMA peptide, based on radiochemical reaction conditions reported previously1. Radiosynthesis was carried out on a FASTlab 2, using developer cassettes and an in-house developed synthesis sequence. 18F-fluoride (~140 GBq) was produced on a GE PETtrace cyclotron employing a 30 min beam at 100 μA. Optimisation studies included the use of dry DMSO, DMF and a DMF:t-butanol (20:80) mixture; different bases including tetrabutylammonium hydrogen carbonate (TBAHCO3), cesium hydrogen carbonate, potassium oxalate and potassium carbonate and different temperatures. The influence of aqueous 0.075M TBAHCO3vs. 0.14M TBAHCO3 in acetonitrile:water on the [18F]PSMA-1007 reaction yield and purity were also studied. The reaction mixture was purified by trapping and elution with 20% ethanol-water through PSH+ and C-18 cartridges in series. Stabilisation of [18F]PSMA-1007 was achieved using sodium ascorbate or sodium thiosulfate. Results: The optimum 18F-radiolabelling conditions were obtained when using 0.14 M TBAHCO3 acetonitrile:water (1:4) as eluent and DMF as the reaction solvent at 95oC for 10 min using 2 mg of the unprotected trimethylammonium pyridinium acetate derivative. The trifluoroacetate and the acetate counterions gave similar radiochemical yields (35-45%). However, the acetate salt resulted in slightly higher radiochemical purity (97-98% vs 95-96%). Aqueous TBAHCO3 (0.075M) eluent also gave high radiochemical purity (>97%), but in a lower radiochemical yield (20-30%). Potassium oxalate in DMF and CsHCO3 also provided [18F]PSMA-1007, but in reduced radiochemical yield (10-20%). Since the reaction uses the unprotected trimethylammonium pyridinium PSMA precursor which involves the deprotonation of five carboxylic acid groups, the concentration and number of base equivalents to the precursor is crucial. We attributed the superior radiochemical yield of [18F]PSMA-1007 to the larger base:precursor ratio and more efficient drying of the 0.14 M TBAHCO3 acetonitrile:water solution. In-line SPE purification, followed by elution with 20% ethanol-water and formulation with phosphate buffer:sodium ascorbate, gave [18F]PSMA-1007 in 30-45% RCY, stable for at least 5 hours post synthesis. Conclusion: [18F]PSMA-1007 can be synthesised in good radiochemical yield (30-45%), non-decay corrected, on a FASTlab 2 using disposable cassettes, in 98% radiochemical purity within 35 min. The synthesis resulted in 30-50 GBq of product from a 30 minute irradiation that will allow it to be used for multiple clinical PET-CT studies. Acknowledgement: We would like to thank Dr Oliver Neels and ABX for their helpful discussions. Reference: J. Cardinale et al. Procedures for the GMP-Compliant Production and Quality Control of [18F]PSMA-1007 - A Next Generation Radiofluorinated Tracer for the Detection of Prostate Cancer. Doi:10.20944/preprints201708.0057v1

To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT.

Blurred boundaries and heterogeneous intensities make accurate prostate MR image segmentation problematic. To improve prostate MR image segmentation we suggest an approach that includes: (a) an image patch division method to partition the prostate into homogeneous segments for feature extraction; (b) an image feature formulation and classification method, using the relevance vector machine, to provide probabilistic prior knowledge for graph energy construction; (c) a graph energy formulation scheme with Bayesian priors and Dirichlet graph energy and (d) a non-iterative graph energy minimization scheme, based on matrix differentiation, to perform the probabilistic pixel membership optimization. The segmentation output was obtained by assigning pixels with foreground and background labels based on derived membership probabilities. We evaluated our approach on the PROMISE-12 dataset with 50 prostate MR image volumes. Our approach achieved a mean dice similarity coefficient (DSC) of 0.90  ±  0.02, which surpassed the five best prior-based methods in the PROMISE-12 segmentation challenge.

The accuracy of five extrathoracic deposition equations was examined by comparing model predictions with in vivo deposition measurements of Tc-99m-DTPA radiolabeled 0.9% saline delivered via PARI LC Sprint nebulizers in 19 healthy human subjects. The average extrathoracic deposition fraction measured in vivo was 0.19 +/- 0.10 (average +/- standard deviation). Comparing to this average value, the extrathoracic deposition fraction predicted by Golshahi et al. equation was the most accurate (0.18 +/- 0.08), followed by the model described by the ICRP (0.16 +/- 0.03). However, prediction of subject-specific deposition proved more challenging; the Golshahi et al. model performed the best of the examined equations, yet showed only a small positive correlation between measured and predicted deposition in individual subjects with a Pearson correlation coefficient of 0.34. The difficulties in predicting subject-specific deposition likely result from geometric dissimilarity both within and between subjects, and may require more complicated modeling methods than algebraic equations of the kind examined in this study.

The present study investigates the effect of DPI resistance and inhalation flow rates on the lung deposition of orally inhaled mannitol dry powder. Mannitol powder radiolabeled with 99mTc-DTPA was inhaled from an Osmohaler™ by healthy human volunteers at 50–70L/min peak inhalation flow rate (PIFR) using both a low and high resistance Osmohaler™, and 110–130L/min PIFR using the low resistance Osmohaler™ (n=9). At 50–70L/min PIFR, the resistance of the Osmohaler™ did not significantly affect the total and peripheral lung deposition of inhaled mannitol [for low resistance Osmohaler™, 20% total lung deposition (TLD), 0.3 penetration index (PI); for high resistance Osmohaler™, 17% TLD, 0.23 PI]. Increasing the PIFR 50–70L/min to 110–130L/min (low resistance Osmohaler™) significantly reduced the total lung deposition (10% TLD) and the peripheral lung deposition (PI 0.21). The total lung deposition showed dependency on the in vitro FPF (R2=1.0). On the other hand, the PI had a stronger association with the MMAD (R2=1.0) than the FPF (R2=0.7). In conclusion the resistance of Osmohaler™ did not significantly affect the total and regional lung deposition at 50–70L/min PIFR. Instead, the total and regional lung depositions are dependent on the particle size of the aerosol and inhalation flow rate, the latter itself affecting the particle size distribution.

2527 Objectives To develop an accurate segmentation method for primary lung tumors, in particular when the tumor has heterogeneous uptake on PET and boundary is difficult to discern on CT. Methods In our MGM, the tumor-background likelihood (TBL) is calculated from CT and the topology information is extracted from PET. The model is developed in 3 stages: Stage 1: Extraction of information including (a) topology to reflect the inclusion or exclusion relation of regions. The topology was extracted by representing PET as a contour tree [1]. (b) TBL was estimated as the joint intensity similarity and spatial distance defined as the shortest Euclidean distance between a pixel and the tumor/background labels. The higher the distance cost, the lower the likelihood of the pixel and the seeds. Stage 2: MGM was constructed with an intensity graph to incorporate PET SUVs for tumor identification and TBL for anatomical boundary delineation. A topology graph, based on the contour tree, provided information for inhomogeneous region grouping; and then an inter-graph was derived to propagate the regional grouping information to pixel level and to provide an appropriate classification of the inhomogeneous FDG distribution within the tumor. Stage 3: Tumor segmentation with MGM used a Random Walk (RW) [2] framework. We validated our method on 40 NSCLC patient datasets with manual delineation by a clinical expert. The volumetric overlap was measured by Dice’s similarity coefficient (DSC). Results Our method achieved a better average DSC of 0.842±0.050, when compared to 7 other approaches including SUV-2.5 (0.671 ± 0.120), 50% SUVmax (0.603 ± 0.098), an adaptive threshold based on mean SUV (0.574 ± 0.193), FCM (0.608 ± 0.209), TCD [4] (0.723 ± 0.086), RW from CT (0.787 ± 0.072) and TBLM [5] from PET-CT (0.813 ± 0.069). Conclusions Our MGM improved segmentation accuracy for the identification of primary lung tumors where the tumors had indistinct margins and where there was inhomogeneous FDG uptake.

Accurate lung tumor segmentation is a prerequisite for effective radiation therapy and surgical planning. However, tumor delineation is challenging when the tumor boundaries are indistinct on PET or CT. To address this problem, we developed a segmentation method to improve the delineation of primary lung tumors from PET–CT images.

Accurate lung tumor segmentation is problematic when the tumor boundary or edge, which reflects the advancing edge of the tumor, is difficult to discern on chest CT or PET. We propose a 'topo-poly' graph model to improve identification of the tumor extent. Our model incorporates an intensity graph and a topology graph. The intensity graph provides the joint PET-CT foreground similarity to differentiate the tumor from surrounding tissues. The topology graph is defined on the basis of contour tree to reflect the inclusion and exclusion relationship of regions. By taking into account different topology relations, the edges in our model exhibit topological polymorphism. These polymorphic edges in turn affect the energy cost when crossing different topology regions under a random walk framework, and hence contribute to appropriate tumor delineation. We validated our method on 40 patients with non-small cell lung cancer where the tumors were manually delineated by a clinical expert. The studies were separated into an 'isolated' group (n = 20) where the lung tumor was located in the lung parenchyma and away from associated structures / tissues in the thorax and a 'complex' group (n = 20) where the tumor abutted / involved a variety of adjacent structures and had heterogeneous FDG uptake. The methods were validated using Dice's similarity coefficient (DSC) to measure the spatial volume overlap and Hausdorff distance (HD) to compare shape similarity calculated as the maximum surface distance between the segmentation results and the manual delineations. Our method achieved an average DSC of 0.881 ± 0.046 and HD of 5.311 ± 3.022 mm for the isolated cases and DSC of 0.870 ± 0.038 and HD of 9.370 ± 3.169 mm for the complex cases. Student's t-test showed that our model outperformed the other methods (p-values <0.05).