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Empirical Versus Dosimetry Approaches.
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Empirical Versus Dosimetry Approaches.

J Nucl Med. 2017 Feb 23;:

Authors: Tulchinsky M, Gross LJ

PMID: 28232615 [PubMed - as supplied by publisher]




Preclinical Evaluation of (18)F-JNJ64349311, a Novel PET Tracer for Tau Imaging.
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Preclinical Evaluation of (18)F-JNJ64349311, a Novel PET Tracer for Tau Imaging.

J Nucl Med. 2017 Feb 23;:

Authors: Declercq LD, Rombouts F, Koole M, Fierens K, Mariën J, Langlois X, Andrés JI, Schmidt ME, Macdonald G, Moechars D, Vanduffel W, Tousseyn T, Vandenberghe R, Van Laere K, Verbruggen A, Bormans GM

Abstract
In this study we have synthesized and evaluated (18)F-JNJ64349311, a tracer with high affinity for aggregated tau (Ki value of 8 nM) and high (≥ 500x) in vitro selectivity for tau over β-amyloid, in comparison with the benchmark compound (18)F-AV1451 ((18)F-T807) in mice, rats and a rhesus monkey. Methods: Using autoradiography studies in vitro binding characteristics were determined on Alzheimer's disease (AD), Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD) patient brain tissue slices. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in brain and plasma of mice and in plasma of a rhesus monkey using high performance liquid chromatography. Dynamic micro positron-emission tomography (µPET) studies were performed in rats and in a rhesus monkey to evaluate tracer pharmacokinetics in brain. Results: Mouse biodistribution studies showed moderate initial brain uptake and rapid brain wash-out. Radiometabolite analyses after injection of (18)F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in brain. Semi-quantitative autoradiography studies on post-mortem tissue sections of human AD brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human PSP and CBD brain slices. µPET-scans on Wistar rats revealed moderate initial brain uptake (standardized uptake value, SUV of ~ 1.5 at 1 min p.i.) and rapid brain wash-out. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in healthy rat brain. A µPET scan on a rhesus monkey revealed moderate initial brain uptake (SUV of 1.9 at 1 min p.i.) with a rapid wash-out. In monkey, no bone uptake was detected during the 120-min scan. Conclusion: This biological evaluation suggests that (18)F-JNJ64349311 is a promising tau PET tracer candidate, with a favourable pharmacokinetic profile as compared to (18)F-AV1451.

PMID: 28232614 [PubMed - as supplied by publisher]




PET imaging for endocrine malignancies: from woe to go.
Related Articles

PET imaging for endocrine malignancies: from woe to go.

J Nucl Med. 2017 Feb 23;:

Authors: Taïeb D, Hicks R, Pacak K

PMID: 28232613 [PubMed - as supplied by publisher]




Reply: Empirical Versus Dosimetry Approaches.
Related Articles

Reply: Empirical Versus Dosimetry Approaches.

J Nucl Med. 2017 Feb 23;:

Authors: Deandreis D, Schlumberger M, Tuttle M

PMID: 28232612 [PubMed - as supplied by publisher]




Pharmacokinetic Analysis of Dynamic (18)F-FMISO PET Data in Non-small Cell Lung Cancer.
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Pharmacokinetic Analysis of Dynamic (18)F-FMISO PET Data in Non-small Cell Lung Cancer.

J Nucl Med. 2017 Feb 23;:

Authors: Schwartz J, Grkovski M, Rimner A, Schoder H, Zanzonico PB, Carlin SD, Staton KD, Humm JL, Nehmeh SA

Abstract
Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. (18)F-fluoromisonidazole (FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. The aim of this study was to perform pharmacokinetic analysis of (18)FMISO dynamic PET (DynFMISO) images of stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Seventeen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 days apart) before radiation therapy (RT): a 3-min static (18)FDG and dynamic (18)FMISO. The dynamic data were acquired in 3 consecutive PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetics software. Compartmental analysis was performed using a 2-tissue, 3-compartment irreversible model and kinetic parameters estimated for all patient/lesion average and voxel-wiseTACs. Results: In this paper, we present results for the average values of FMISO kinetic parameters for NSCLC lung lesions, as well as non-tumorous lung and muscle tissues. We also investigate the correlation between the trapping rate (k3) and (a) perfusion rate (K1), (b) influx rate (Ki) and (c) and tumor-to-blood ratio (TBR) for all tissues. On average, lesions had trapping rates that were an average of 1.6 times larger than those in normal lung tissues and 4.4 times larger than in muscle tissues. Additionally, for almost all cases, k3 and Ki had a significant strong correlation for all tissue types. The correlation between TBR and k3 was more ambiguous, showing a strong correlation for only 41% of the targets studied. Finally, K1 - k3 pixel-wise correlations for tumors were varied, but negative for 76% of lesions, with a globally weak inverse relationship (average R = -0.25 ± 0.37). This was markedly different both normal tissue types, which were positive for 62.5% of the patients; 38% of those exhibited moderate to high correlations, as R > 0.5. Conclusion: All lesions were FMISO avid. The lesions in all patients exhibited relatively high perfusion, as indicated by the kinetic rate constant K1. For all patients, tumors exhibited some degree of hypoxia as evidenced by the nonzero k3 values.

PMID: 28232611 [PubMed - as supplied by publisher]




Reply to Letter from Carol S. Marcus.
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Reply to Letter from Carol S. Marcus.

J Nucl Med. 2017 Feb 23;:

Authors: Weber WA, Zanzonico P

PMID: 28232610 [PubMed - as supplied by publisher]




Imaging of the Cardiac Sympathetic Nervous System Has Potential Value in the Evaluation of Patients with HFpEF.
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Imaging of the Cardiac Sympathetic Nervous System Has Potential Value in the Evaluation of Patients with HFpEF.

J Nucl Med. 2017 Feb 23;:

Authors: Boutagy NE, Sinusas AJ

PMID: 28232609 [PubMed - as supplied by publisher]




Metabolic Imaging of Glutamine in Cancer.
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Metabolic Imaging of Glutamine in Cancer.

J Nucl Med. 2017 Feb 23;:

Authors: Kung HF, Ploessl K, Mankoff D, Zhu L, Zhou R

Abstract
Glucose and glutamine are the most abundant nutrients for producing energy and building blocks in normal and tumor cells. Increased glycolysis in tumors, "Warburg Effect", is the basis for (18)F-FDG/PET imaging. Cancer cells can also be genetically reprogrammed to use glutamine. 5-(11)C-(2S)-glutamine and (18)F- (2S,4R)4-fluoroglutamine may be useful complementary tools to measure changes in tumor metabolism. In glioma patients the tracer, (18)F-(2S,4R)4-fluoroglutamine, showed tumor-background contrast different from that of (18)F-FDG and differences in uptake in glioma patients with clinical progression of disease versus stable disease (tumor/brain ratio > 3.7 in clinically active glioma tumors, minimal or no specific uptake in clinically stable tumors). These preliminary results suggest that (18)F-(2S,4R)4-fluoroglutamine/PET may be a new tool for probing in vivo metabolism of glutamine in cancer patients and for guiding glutamine-targeted therapeutics. Further studies of uptake mechanism, and comparison of kinetics for (18)F-(2S,4R)4-fluoroglutamine versus the (11)C labeled native glutamine will be important and enlightening.

PMID: 28232608 [PubMed - as supplied by publisher]




PET Imaging Evaluation of Four Novel Sigma-1 Radiotracers in Nonhuman Primates.
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PET Imaging Evaluation of Four Novel Sigma-1 Radiotracers in Nonhuman Primates.

J Nucl Med. 2017 Feb 23;:

Authors: Baum EJ, Cai Z, Bois F, Holden D, Lin SF, Lara-Jamie T, Kapinos M, Chen YY, Deuther-Conrad W, Fischer S, Dukic-Stefanovic S, Bunse P, Wünsch B, Brust P, Jia H, Huang Y

Abstract
Sigma-1 receptors (S1R) are implicated in a variety of diseases including Alzheimer's disease and cancer. Previous positron emission tomography (PET) S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of four (18)F-labeled spirocyclic piperidine-based PET radiotracers ((18)F-1 to (18)F-4). Methods: Baseline scans for the four radiotracers were obtained on an adult male rhesus monkey. Blocking scans were performed with the S1R agonist SA4503 to assess binding specificity of (18)F-2 and (18)F-4. Arterial input functions were measured and binding parameters were determined with kinetic modeling analysis. Results: In the rhesus brain, all four radiotracers showed high and fast uptake. Tissue activity washout was rapid for (18)F-2 and (18)F-4, and much slower for (18)F-1 and (18)F-3, in line with their respective in vitro S1R binding affinities. Both the 1-tissue compartment (1TC) and multilinear analysis-1 (MA1) kinetic models provided good fits of time-activity curves (TACs) and reliable estimates of distribution volume (VT). Regional VT values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. (18)F-4 showed greater differential uptake across brain regions and three-fold higher binding potential (BPND) than (18)F-2. SA4503 at the dose of 0.5 mg/kg blocked ~85% ((18)F-2) and ~95% ((18)F-4) of radiotracer binding. Conclusion: Tracers (18)F-2 and (18)F-4 displayed high brain uptake and fast tissue kinetics, with (18)F-4 having higher specific binding signals than (18)F-2 in the same monkey. Taken together, these data indicate that both radiotracers (18)F-2 and (18)F-4 possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the primate brain.

PMID: 28232607 [PubMed - as supplied by publisher]




Association between osteogenesis and inflammation during the progression of calcified plaque as evaluated by combined (18)F-NaF and (18)F-FDG PET/CT.
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Association between osteogenesis and inflammation during the progression of calcified plaque as evaluated by combined (18)F-NaF and (18)F-FDG PET/CT.

J Nucl Med. 2017 Feb 23;:

Authors: Li X, Heber D, Cal Gonzales J, Karanikas G, Mayerhoefer ME, Rasul S, Beitzke D, Zhang X, Agis H, Mitterhauser M, Wadsak W, Beyer T, Loewe C, Hacker M

Abstract
Background and Aim:(18)F-fluorodeoxyglucose ((18)F-FDG) is the most widely validated positron emission tomography (PET) tracer for the evaluation of atherosclerotic inflammation. (18)F-sodium fluoride ((18)F-NaF) has also been recently considered a potential novel biomarker of osteogenesis in atherosclerosis. We aimed to analyze the association between inflammation and osteogenesis at different stages of atherosclerosis, as well as the interrelationship between these two processes during disease progression. Methods: Thirty-four myeloma patients underwent (18)F-NaF and (18)F-FDG PET/computed tomography (CT) examinations. Three groups (non-calcified; mildly calcified; and severely calcified lesions) were divided based on the calcium density as measured in Hounsfield units (HU) by CT. Tissue-to-background ratios (TBR) were determined from PET for both tracers. The association between inflammation and the osteogenesis during atherosclerosis progression was evaluated in 19 patients who had at least two examinations with both tracers. Results: There were significant correlations between the TBRmax values of the two tracers (Spearman's r = 0.5, P < 0.01, Pearson r = 0.4, P < 0.01) in the 221 lesions at baseline. In non-calcified lesions, highest uptake of both tracers was observed, but without any correlation between both tracers (Pearson r = 0.06, P = 0.76). Compared to non-calcified plaques, concordant significantly lower accumulation was found in mildly calcified plaques, with good correlation between the tracers (Pearson r = 0.7, P < 0.01). In addition, there was enhanced osteogenesis-derived (18)F-NaF uptake, and regressive inflammation-derived (18)F-FDG uptake in severely calcified lesions (Pearson r = 0.4, P < 0.01). During follow-up, there was an increased calcium density and an increased mean (18)F-NaF uptake observed, while the mean (18)F-FDG uptake decreased. The majority of non-calcified (86%) and mildly calcified (81%) lesions and 47% of severely calcified lesions had a concordant development of both vascular inflammation and osteogenesis. Conclusion: The combination of (18)F-NaF and (18)F-FDG PET imaging promotes an understanding of the mechanism of plaque progression, thereby providing new insights into plaque stabilization.

PMID: 28232606 [PubMed - as supplied by publisher]




Repeatability of Standardized Uptake Value in Oncologic (18)F-FDG PET.
Related Articles

Repeatability of Standardized Uptake Value in Oncologic (18)F-FDG PET.

J Nucl Med. 2017 Feb 23;:

Authors: Lodge MA

Abstract
Quantitative analysis can potentially improve the accuracy and consistency of 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET), particularly for the assessment of tumor response to treatment. Although not without limitations, standardized uptake value (SUV) has emerged as the predominant metric for tumor quantification with (18)F-FDG PET. Growing literature suggests that the difference between SUVs measured before and after treatment can be used to predict tumor response at an early stage. SUV is, however, associated with multiple sources of variability and in order to best use SUV for response assessment, an understanding of the repeatability of the technique is required. Test-retest studies involve repeated scanning of the same patient on the same scanner, using the same protocol, no more than a few days apart, and provide basic information on the repeatability of the technique. Multiple test-retest studies have been performed to assess SUV repeatability, although a comparison of reports is complicated by the use of different methodology and statistical metrics. This article reviews the available data, addressing issues such as different repeatability metrics, relative units, log transformation and asymmetric limits of repeatability. When acquired with careful attention to protocol, tumor SUV has a within-subject coefficient-of-variation (wCV) of approximately 10 %. In a response assessment setting, SUV reductions by more than 25 % and increases by more than 33 % are unlikely to be due to measurement variability. Broader margins may be required for sites with less rigorous protocol compliance but, in general, SUV is a highly repeatable imaging biomarker that is ideally suited for monitoring tumor response to treatment in individual patients.

PMID: 28232605 [PubMed - as supplied by publisher]




Alpha- versus beta-emitting radionuclides for pretargeted radioimmunotherapy of CEA-expressing human colon cancer xenografts.
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Alpha- versus beta-emitting radionuclides for pretargeted radioimmunotherapy of CEA-expressing human colon cancer xenografts.

J Nucl Med. 2017 Feb 23;:

Authors: Heskamp S, Hernandez R, Molkenboer-Kuenen JD, Essler M, Bruchertseifer F, Morgenstern A, Steenbergen E, Cai W, Seidl C, McBride W, Goldenberg D, Boerman O

Abstract
Rational: Pretargeted radionuclide therapy (PRIT) with the beta-emitting radionuclide (177)Lu is an attractive approach to treat CEA-expressing tumors. The therapeutic efficacy of PRIT could be improved by using alpha-emitting radionuclides such as (213)Bi. Herein, we report and compare the tumor targeting properties and therapeutic efficacy of (213)Bi and (177)Lu for PRIT of CEA-expressing xenografts, using the bispecific antibody TF2 (anti-CEA x anti-HSG) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of (213)Bi-IMP288 were compared with those of (177)Lu-IMP288. Tumor targeting of (213)Bi-IMP288 and (177)Lu-IMP288 was studied in mice bearing subcutaneous (s.c.) LS174T tumors that were pretargeted with the bispecific antibody TF2. Finally, the effect of (213)Bi-IMP288 (6, 12, or 17 MBq) and (177)Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for haematological and renal toxicity (haemoglobin, leucocytes, platelets, creatinine), and by immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of (213)Bi-IMP288 (Kd = 0.45 ± 0.20 nM) to TF-2 pretargeted LS174T cells were similar to those of (177)Lu-IMP288 (Kd = 0.53 ± 0.12 nM). In vivo accumulation of (213)Bi-IMP288 in LS174T tumors was observed as early as 15 min post injection (9.2 ± 2.0 %ID/g). (213)Bi-IMP288 cleared rapidly from the circulation; at 30 min post injection the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was very low, except for the kidneys where uptake was 1.8 ± 1.1 %ID/g, at 30 min p.i. The biodistribution of (213)Bi-IMP288 was comparable to that of (177)Lu-IMP288. Mice treated with a single dose of (213)Bi-IMP288 or (177)Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the PBS, 6 MBq (213)Bi-IMP288, 12 MBq (213)Bi-IMP288, and 60 MBq (177)Lu-IMP288 treated groups was 22, 31, 45, and 42 days, respectively. Mice receiving 17 MBq (213)Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 days. No changes in haemoglobin, platelets, and leucocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq (213)Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: This study showed, for the first time, that PRIT with TF2 and (213)Bi-IMP288 is feasible and comparable to (177)Lu-IMP288 in terms of effectiveness. However, at the higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve the therapeutic efficacy while reducing renal toxicity.

PMID: 28232604 [PubMed - as supplied by publisher]