Characterization Of [11C]-GSK1482160 For Targeting The P2X7 Receptor As A Biomarker For Neuroinflammation.
J Nucl Med. 2016 Oct 20;:
Authors: Territo PR, Meyer JA, Peters JS, Riley AA, McCarthy BP, Gao M, Wang M, Green MA, Zheng QH, Hutchins GD
BACKGROUND: The P2X7 receptor represents a novel molecular target for imaging neuroinflammation via PET. GSK1482160, a potent P2X7 receptor antagonist, has high receptor affinity, blood-brain barrier penetration, and has been recently radiolabel ((11)C-GSK1482160). Therefore, we report the initial physical and biological characterization of this novel ligand.
METHODS: (11)C-GSK1482160 synthesis was according to published methods. Cell density studies were performed in human embryonic kidney cell lines expressing human P2X7 receptors (HEK293-hP2X7R) and analyzed by western blot analysis, immuno-fluorescence assay (IFA), and radiologic-immunohistochemistry (RIHC) using P2X7R polyclonal antibodies. Receptor density (Bmax) and binding potential (Bp) were determined by saturation and association/disassociation kinetics, respectively. Peak immune response to lipopolysaccharide (LPS) stimuli in mice were determined in time course studies and analyzed via Iba1 and P2X7R western blot and Iba1 IHC. Whole animal biodistribution was performed in untreated mice or LPS at 15, 30, and 60min post radiotracer administration. Dynamic in vivo PET/CT was performed in mice administered saline, LPS, or LPS+blocking at 72 hr, and brain regions modeled using a 2 compartment 5 parameter tracer kinetic model.
RESULTS: P2X7R linearly changed with concentrations and/or cell numbers. Using high specific activity (11)C-GSK1482160, Bmax and Kd were 1.15±0.12nM and 3.03±0.10 pmol/mg in HEK293-hP2X7R membranes, respectively. Determination of kon, koff, and Bp in HEK293-hP2X7R cells were 0.2312±0.01542 min-1.nM-1, 0.2547±0.0155 min-1, 1.0277±0.207, respectively. Whole brain Iba1 expression in LPS stimulated mice peaked by 72 hr. IHC and western blot analysis of P2X7R for saline and LPS brain sections showed a 1.8 and 1.7 fold increase in signal enhancement at 72 hr, respectively. Biodistribution of (11)C-GSK1482160 in untreated and LPS treated mice at 72 hr were statistically significant across all tissues studied. In vivo dynamic (11)C-GSK1482160 PET/CT in mice administered saline, LPS, or LPS+blocking at 72 hr resulted in a 3.2 fold increase and 97% blocking by 30 min. Total volumes of distributions (V_T) for multiple cortical regions and the hippocampus showed statistically significant increases, and were blocked by excess authentic standard GSK1482160.
CONCLUSION: The current study provides compelling data that supports (11)C-GSK1482160 is suitable as a novel radioligand targeting P2X7 receptors as a biomarker of neuroinflammation.
PMID: 27765863 [PubMed - as supplied by publisher]
German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients.
J Nucl Med. 2016 Oct 20;:
Authors: Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schäfers M, Essler M, Baum RP, Kulkarani HR, Schmidt M, Bartenstein P, Pfestroff A, Lützen U, Marx M, Prasad V, Brenner W, Heinzel A, Ruf J, Meyer PT, Heuschkel M, Eveslage M, Bögemann M, Fendler WP, Krause BJ
(177)Lutetium labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of (177)Lu-PSMA-617 in a large cohort of patients.
METHODS: 145 patients (median age 73 years, range 43-88) with mCRPC were treated with (177)Lu-PSMA-617 in 12 therapy centres between February 2014 and July 2015 with one to four therapy cycles and an activity range of 2 to 8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (CTCAE 4.0) based on serial blood tests and the attending physician's report. Primary endpoint for efficacy was biochemical response as defined by a PSA decline ≥ 50% from baseline to at least two weeks after start of RLT.
RESULTS: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response were available in 99 patients and data for physician-reported/lab-based toxicity in 145/121 patients. The median follow-up was 16 weeks (range 2-30 weeks). Nineteen patients died during the observation period. Grade 3 to 4 hematotoxicity occurred in 18 patients: 10%, 4% and 3% of the patients experienced anemia, thrombocytopenia and leukopenia, respectively. Xerostomia occurred in 8%. Overall biochemical response rate was 45% following all therapy cycles, while 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response.
CONCLUSION: The present retrospective multicenter study of (177)Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third line systemic therapies in mCRPC patients. Future Phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.
PMID: 27765862 [PubMed - as supplied by publisher]
Brain FDG-PET metabolic abnormalities in patients with long-lasting macrophagic myofasciitis.
J Nucl Med. 2016 Oct 20;:
Authors: Van Der Gucht A, Aoun Sebaiti M, Guedj E, Aouizerate J, Yara S, Gherardi R, Evangelista E, Chalaye J, Cottereau AS, Verger A, Bachoud-Levi AC, Itti E, Authier FJ
PURPOSE: Macrophagic myofasciitis (MMF) is an emerging condition with specific muscle lesions characterized by an abnormal long-term persistence of aluminum hydroxide particles within macrophages at the site of previous immunization. Patients present with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. The aim of this study was to characterize brain FDG-PET metabolic abnormalities in MMF patients, and the relation with cognitive dysfunction.
METHODS: FDG-PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (mean age, 45.9 ± 11.8 y; women, 74%) followed in our Reference Center for Rare Neuromuscular Diseases. Images were analyzed using statistical parametric mapping (SPM12). Using ANCOVA analysis, all FDG-PET brain images of MMF patients were compared to a reference population of 44 healthy subjects matched for age (mean age, 45.4 ± 16 y; P = 0.87) and gender (women, 73%; P = 0.88). All results were collected at a P-value < 0.005 at the voxel level, for clusters k ≥ 200 voxels (corrected for cluster volume) with adjustment for age and gender. The neuropsychological assessment identified four categories of patients with: (i) no significant cognitive impairment (n = 42); (ii) frontal sub-cortical (FSC) dysfunction (n = 29); (iii) papezian dysfunction (n = 22); and (iv) callosal disconnection (n = 7).
RESULTS: In comparison with healthy subjects, ANCOVA analysis of the whole population of patients with MMF exhibited a pattern of hypometabolism (p<0.001) involving occipital lobes, temporal lobes, limbic system, cerebellum and frontoparietal cortices. The subgroup of patients with FSC dysfunction exhibited larger extents of involved area (35223 voxels vs. 13680 voxels in the subgroup with papezian dysfunction and 5453 voxels in patients without cognitive impairment). Not significant result was obtained in the last subgroup due to its small population size.
CONCLUSION: Our study identified in MMF patients a peculiar patterm of a cerebral glucose hypometabolism mostly marked in MMF patients with FSC dysfunction. This characteristic pattern could reprensent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction.
PMID: 27765861 [PubMed - as supplied by publisher]
Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Non-Thyroid Tissues.
J Nucl Med. 2016 Oct 20;:
Authors: Langen B, Rudqvist N, Helou K, Forssell-Aronsson EB
INTRODUCTION: Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation resulting in a certain percentage of free radionuclide in the body. The radiohalogen (211)At accumulates in various tissues with specifically high uptake in the thyroid. When normal thyroid function is disturbed due to ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiological function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from (211)At (Langen et al. JNM, 2013). Here, we present supportive evidence on systemic effects after (211)At administration.
METHODS: Expression microarray data from kidney cortex and medulla, liver, lungs, and spleen were used from previous studies where mice were i.v. injected with 0.064-42 kBq (211)At and killed after 24 h, or injected with 1.7 kBq (211)At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software.
RESULTS: Responses in IR- or TH-associated gene signatures were tissue-specific, varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least similar extent as the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream-regulators with differences in incidence and strength of regulation depending on tissue type.
CONCLUSION: These findings indicate that transcriptional regulation in various non-thyroid tissues was-in part-induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.
PMID: 27765860 [PubMed - as supplied by publisher]
Modeling strategies for quantification of in vivo 18F-AV1451 binding in patients with tau pathology.
J Nucl Med. 2016 Oct 20;:
Authors: Hahn A, Schain M, Erlandsson M, Sjölin P, James GM, Strandberg OT, Hägerström D, Lanzenberger R, Jögi J, Olsson TG, Smith R, Hansson O
Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer's disease. In vivo imaging with positron emission tomography (PET) may offer important insights in pathophysiological mechanisms, diagnosis and disease progression. We describe different strategies for quantification of (18)F-AV1451 (T807) tau binding, including models with blood sampling and non-invasive alternatives.
METHODS: 15 subjects (4 controls, 6 Alzheimer's disease (AD), 3 progressive supranuclear palsy (PSP), 2 cortico basal syndrome (CBS)) underwent 180 min PET with (18)F-AV1451 and arterial blood sampling. Modeling with arterial input functions included one-, two- and three-tissue compartment models and the Logan plot. Using cerebellum as reference region, the simplified reference tissue model 2 and Logan reference plot were applied. Finally, simplified outcome measures were calculated as ratio with reference to cerebellum concentrations (SUVR) and standard uptake values.
RESULTS: Tissue compartment models were not able to describe the kinetics of (18)F-AV1451 with poor fits in 33-53% of cortical regions and 80% in subcortical areas. In contrast, Logan plot showed excellent fits and parameter variance (VT standard error < 5%). Compared to the 180 min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for reduced scan time of 100 min (R2 = 0.91) and SUVR 100-120 min (R2 = 0.94), with 80-100min already representing a reasonable compromise between duration and accuracy (R2 = 0.93). Time activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects, but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For the above methods, increased cortical binding was observed for AD patients and to some extent for CBS, but not PSP.
CONCLUSION: Using arterial input functions, the Logan plot provided the best estimate of tau binding. Assuming that cerebellum is a valid reference region, simplified methods seem to provide robust alternatives for quantification, such as the Logan reference plot with 100 min scan time. Furthermore, SUVR ratios between target and cerebellar activities obtained from a 80-100 min static scan offer promising potential for clinical routine application.
PMID: 27765859 [PubMed - as supplied by publisher]
Metabolic evaluation of non-small cell lung cancer patient-derived xenografts models using [18F]FDG PET: potential tools for early therapy response.
J Nucl Med. 2016 Oct 20;:
Authors: Valtorta S, Moro M, Prisinzano G, Bertolini G, Tortoreto M, Raccagni I, Pastorino U, Roz L, Sozzi G, Moresco RM
PURPOSE: Lung cancer heterogeneity makes response to therapy extremely hard to predict. Patient-derived xenografts (PDXs) represent a reliable preclinical model that closely recapitulates the main characteristics of the primary tumor and could represent a useful asset to test new therapies. Here, using PET imaging, we verify how lung cancer PDXs reproduce the metabolic features of the corresponding primary tumors.
METHODS: We performed longitudinal [(18)F]FDG-PET studies on nine different PDXs, obtained by implants of primary cancer fragments harvested from patients. Max [(18)F]FDG uptake values of the lesion for each group were calculated and compared to corresponding patient's uptake.
RESULTS: Different PDXs showed variable tumor growth rate and [(18)F]FDG uptake confirming the preservation of individual characteristics. A good intra-group reproducibility of PET measurements was observed. Furthermore, the subgroup of PDXs originating from primary tumors with higher metabolic rate displayed a rank order of [(18)F]FDG uptake similar to that of patients' original SUV.
CONCLUSION: PDXs reproduced the original glucose metabolism of primary lesions and represent therefore a promising preclinical model also for the early assessment of therapy efficacy.
PMID: 27765858 [PubMed - as supplied by publisher]
Assessment of tryptophan uptake and kinetics using 1-(2-[18F]fluoroethyl)-L-tryptophan and α-[11C]-methyl-L-tryptophan PET imaging in mice implanted with patient-derived brain tumor xenografts.
J Nucl Med. 2016 Oct 20;:
Authors: Michelhaugh SK, Muzik O, Guastella AR, Klinger NV, Polin LA, Cai H, Xin Y, Mangner TJ, Zhang S, Juhasz C, Mittal S
Abnormal tryptophan metabolism via the kynurenine pathway (KP) is involved in the pathophysiology of a variety of human diseases including cancers. α-[(11)C]-methyl-L-tryptophan ((11)C-AMT) positron emission tomography (PET) imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of (11)C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-[(18)F]fluoroethyl)-L-tryptophan ((18)F-FETrp) may be useful to assess tryptophan metabolism via the KP. In this study, we tested in vivo organ and tumor uptake and kinetics of (18)F-FETrp in patient-derived xenograft mouse models and compared it with (11)C-AMT uptake.
METHODS: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with (18)F-FETrp and (11)C-AMT were performed on mice bearing human brain tumors 1-7 days apart. The biodistribution and tumoral standardized uptake values (SUVs) for both tracers were compared.
RESULTS: (18)F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas (11)C-AMT showed higher uptake in kidneys. Both tracers showed uptake in the xenograft tumors with a plateau ~30-min post-injection; however, (18)F-FETrp showed higher tumoral SUV than (11)C-AMT in all three tumor types tested. The radiation dosimetry for (18)F-FETrp determined from the mouse data compared favorably to the clinical 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) PET tracer.
CONCLUSION: (18)F-FETrp tumoral uptake, biodistribution and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly-applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.
PMID: 27765857 [PubMed - as supplied by publisher]
Reliability of PET/CT shape and heterogeneity features in functional and morphological components of Non-Small Cell Lung Cancer tumors: a repeatability analysis in a prospective multi-center cohort.
J Nucl Med. 2016 Oct 20;:
Authors: Desseroit MC, Tixier F, Weber WA, Siegel BA, Cheze Le Rest C, Visvikis D, Hatt M
PURPOSE: The main purpose of this study was to assess the reliability of shape and heterogeneity features in both PET and low-dose CT components of PET/CT. A secondary objective was to investigate the impact of image quantization.
MATERIAL AND METHODS: A HIPAA-compliant secondary analysis of deidentified prospectively acquired PET/CT test-retest datasets of 74 patients from multi-center Merck and ACRIN trials was performed. Metabolically active volumes were automatically delineated on PET with Fuzzy Locally Adaptive Bayesian (FLAB) algorithm. 3DSlicer™ was used to semi-automatically delineate the anatomical volumes on low-dose CT components. Two quantization methods were considered: a quantization into a set number of bins (quantizationB) and an alternative quantization with bins of fixed width (quantizationW). Four shape descriptors, ten first-order metrics and 26 textural features were computed. Bland-Altman analysis was used to quantify repeatability. Features were subsequently categorized as very reliable, reliable, moderately reliable and poorly reliable with respect to the corresponding volume variability.
RESULTS: Repeatability was highly variable amongst features. Numerous metrics were identified as poorly or moderately reliable. Others were (very) reliable in both modalities, and in all categories (shape, 1(st)-, 2(nd)- and 3(rd)-order metrics). Image quantization played a major role in the features repeatability. Features were more reliable in PET with quantizationB, whereas quantizationW showed better results in CT.
CONCLUSION: The test-retest repeatability of shape and heterogeneity features in PET and low-dose CT varied greatly amongst metrics. The level of repeatability also depended strongly on the quantization step, with different optimal choices for each modality. The repeatability of PET and low-dose CT features should be carefully taken into account when selecting metrics to build multiparametric models.
PMID: 27765856 [PubMed - as supplied by publisher]
Molecular Drug Imaging: 89Zr-bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma.
J Nucl Med. 2016 Oct 20;:
Authors: Jansen M, Veldhuijzen van Zanten SE, Van Vuurden DG, Huisman M, Vugts DJ, Hoekstra OS, van Dongen GA, Kaspers GJ
Predictive tools to guide therapy in children with brain tumors are urgently needed. We introduced molecular imaging to facilitate this. We investigated whether bevacizumab can reach the tumor in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of zirconium-89((89)Zr)-labeled bevacizumab by PET. In addition we evaluated the safety of the procedure in children and determined the optimal timing of imaging.
METHODS: Patients received 0.1 mg/kg (0.9 MBq/kg) (89)Zr-bevacizumab, ≥ two weeks after completing radiotherapy. Whole body PET-CT scans were performed 1, 72 and 144 hours post-injection (p.i.). All patients underwent contrast (gadolinium)-enhanced MRI. Biodistribution of (89)Zr-bevacizumab was quantified as Standardized Uptake Values (SUVs).
RESULTS: We included seven DIPG patients (4 males, age range 6-17 years) who were scanned without anesthesia. No adverse events occurred. Five out of seven primary tumors showed focal (89)Zr-bevacizumab uptake (SUVs range 1.0-6.7 at 144 hours p.i.), while there was no significant uptake in healthy brain. One patient had multiple metastases, which were all PET positive. There was inter- and intra-tumoral heterogeneity of uptake and (89)Zr-bevacizumab was predominantly (in 4 out of 5 patients) present within the MRI contrast-enhancing areas, although (89)Zr-bevacizumab uptake was variable among MRI contrast-enhancing areas. Tumor targeting was quantitatively similar at 72 and 144 hours post-injection, but tumor-to-blood SUV ratios increased over post-injection time (P = 0.045). The mean effective dose per patient was 0.9±0.3 mSv/MBq.
CONCLUSION: (89)Zr-bevacizumab PET-studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery between patients and within DIPG tumors and a positive, but not 1-to-1, correlation between MRI contrast-enhancement and (89)Zr-bevacizumab uptake. The optimal moment of scanning is 144 hours p.i.. Tumor (89)Zr-bevacizumab accumulation as assessed by PET scanning might help to select patients with highest chance of benefit from bevacizumab treatment.
PMID: 27765855 [PubMed - as supplied by publisher]