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pubmed: 0161-5505



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Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life-Span of Wild-Type Mice: A PET Study.

Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life-Span of Wild-Type Mice: A PET Study.

J Nucl Med. 2017 Jul 13;:

Authors: Brendel M, Focke C, Blume T, Peters F, Deussing M, Probst F, Jaworska A, Overhoff F, Albert N, Lindner S, von Ungern-Sternberg B, Bartenstein P, Haass C, Kleinberger G, Herms J, Rominger A

Abstract
Contrary to findings in human brain, [(18)F]-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual tracer µPET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. Methods: WT mice (5-20 months) were investigated in a cross-sectional design using [(18)F]-FDG (N = 43) and TSPO ([(18)F]-GE180; N = 58) µPET, with volume-of-interest and voxel-wise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. Results: Age-dependent cortical hypermetabolism in WT mice relative to young animals aged five months peaked at 14.5 months (+16%,p<0.001), and declined to baseline at 20 months. Similarly, cortical TSPO binding increased to a maximum at 14.5 months (+15%, p<0.001), and remained high to 20 months, resulting in an overall correlation between [(18)F]-FDG uptake and TSPO binding (β=0.61; p<0.05). Biochemical and immunohistochemical analyses confirmed the TSPO µPET findings. Conclusion: Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice.

PMID: 28705919 [PubMed - as supplied by publisher]




In vivo quantification of ER-β expression by pharmacokinetic modeling: Studies with (18)F-FHNP PET.

In vivo quantification of ER-β expression by pharmacokinetic modeling: Studies with (18)F-FHNP PET.

J Nucl Med. 2017 Jul 13;:

Authors: Antunes IF, Willemsen ATM, Sijbesma JWA, Boerema AS, van Waarde A, Glaudemans AWJM, Dierckx RA, de Vries EGE, Hospers GAP, de Vries EF

Abstract
The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2-(18)F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol ((18)F-FHNP) for assessment of ERβ levels with positron emission tomography (PET). Here we investigated several pharmacokinetic analysis methods to quantify changes in ERβ availability with (18)F-FHNP-PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERβ-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic (18)F-FHNP-PET scan with arterial blood sampling was acquired in rats treated with vehicle or various concentrations of estradiol (non-specific ER agonist) or genistein (ERβ selective agonist). Different pharmacokinetic models were applied to quantify ERβ availability in the tumor. Results: Irreversible uptake compartment models fitted the kinetics of (18)F-FHNP uptake better than reversible models. The irreversible 3-tissue compartment model, which included both the parent and the metabolite input function, gave comparable results as the irreversible 2-tissue compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave comparable metabolic rates (Ki) as compartment modeling. The Ki values correlated well with ERβ expression, but not with ERα, confirming that Ki is a suitable parameter to quantify ERβ expression. Standardized uptake values at 60 minutes after tracer injection also correlated (r2=0.47; P = 0.04) with ERβ expression. A reduction in (18)F-FHNP tumor uptake and Ki values was observed in the presence of estradiol or genistein. Conclusion:(18)F-FHNP-PET enables assessment of ERβ availability in tumor-bearing rats. The most suitable parameter to quantify ERβ expression is the Ki. However, a simplified static imaging protocol for determining the SUV can be applied to assess ERβ levels, if somewhat lower accuracy is acceptable.

PMID: 28705918 [PubMed - as supplied by publisher]




Curative multi-cycle radioimmunotherapy monitored by quantitative SPECT/CT-based theranostics, using bispecific antibody pretargeting strategy in colorectal cancer.

Curative multi-cycle radioimmunotherapy monitored by quantitative SPECT/CT-based theranostics, using bispecific antibody pretargeting strategy in colorectal cancer.

J Nucl Med. 2017 Jul 13;:

Authors: Cheal SM, Fung EK, Patel MV, Punzalan B, Xu H, Guo HF, Zanzonico PB, Monette S, Wittrup KD, Cheung NK, Larson SM

Abstract
Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TI). We recently reported a novel three-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody (bsAb) and a small-molecule radioactive hapten, a complex of lutetium-177 ((177)Lu) and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid ((177)Lu-DOTA-Bn) that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We tested our hypothesis that a fractionated anti-GPA33 DOTA-PRIT treatment regimen calibrated to deliver a radiation-absorbed dose to tumor >100 Gy would lead to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-postitive SW1222 xenografts. Methods: We treated groups of nude mice bearing 7-day-old SW1222 xenografts with a fractionated three-cycle anti-GPA33 DOTA-PRIT treatment regimen (total administered (177)Lu-DOTA-Bn activity: 167 MBq/mouse; estimated radiation-absorbed dose to tumor: 110 Gy). In randomly selected mice undergoing treatment, serial single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was used to monitor treatment response and calculate radiation-absorbed doses to tumor. Necropsy was done on surviving animals 100-200 days post-treatment to determine frequency of cure and assess select normal tissues for treatment-related histopathologies. Results: Rapid exponential tumor progression was observed in control treatment groups (i.e., no treatment or (177)Lu-DOTA-Bn only), leading to euthanasia due to excessive tumor burden, while 10/10 complete responses were observed for the DOTA-PRIT treated animals within 30 days. Treatment was well tolerated and 100% histologic cure in 9/9 assessable animals without detectable radiation damage to critical organs, including bone marrow and kidney. Radiation-absorbed doses to tumor derived from SPECT/CT (102 Gy) and from biodistribution (110 Gy) agreed to within 6.9%. Of the total dose of ~100 Gy, the first dose contributes 30%, the second dose 60%, and the third dose 10%. Conclusion: In a GPA33-positive human colorectal cancer (CRC) xenograft mouse model, we validated a SPECT/CT-based theranostic PRIT regimen that led to 100% complete responses and 100% cures without any treatment-related toxicities, based on high TIs for radiosensitive tissues. These studies support the view that anti-GPA33 DOTA-PRIT will be a potent radioimmunotherapy regimen for GPA33-positive CRC tumors in man.

PMID: 28705917 [PubMed - as supplied by publisher]




Biodistribution and dosimetry of (18)F-Meta Fluorobenzyl Guanidine (MFBG): A first-in-human PET-CT imaging study of patients with neuroendocrine malignancies.

Biodistribution and dosimetry of (18)F-Meta Fluorobenzyl Guanidine (MFBG): A first-in-human PET-CT imaging study of patients with neuroendocrine malignancies.

J Nucl Med. 2017 Jul 13;:

Authors: Pandit-Taskar N, Zanzonico PB, Staton KD, Carrasquillo JA, Reidy-Lagunes D, Lyashchenko SK, Burnazi E, Zhang H, Lewis JS, Blasberg R, Larson SM, Weber WA, Modak S

Abstract
Introduction: Iodine-123-meta-iodobenzylguanidine ((123)I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. (123)I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. (18)F-MFBG is a positron emission tomography (PET) analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of (18)F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of (18)F-MFBG in neuroendocrine tumors (NETs). Methods: Ten patients (five with neuroblastoma and five with paraganglioma/ pheochromocytoma) received 148-444 MBq (4-12 mCi) of (18)F-MFBG IV followed by serial whole-body imaging at 0.5-1 h, 1-2 h, and 3-4 h post-injection (p.i.). Serial blood samples (a total of 6) were also obtained starting at 5 min p.i. to as late as 4 h p.i. whole-body distribution and blood clearance data, lesion uptake, and normal tissue uptakes were determined; radiation-absorbed doses to normal organs were calculated using Organ Level INternal Dose Assessment (OLINDA). Results: No side effects were seen in any patient after (18)F-MFBG injection. Tracer distribution showed prominent activity in bloodpool, liver, and salivary glands that decreased with time. Mild uptake was seen in kidneys and spleen, which also decreased with time. Urinary excretion was prominent, with an average of 45% of the administered activity in bladder by 1 h p.i. whole-body clearance was monoexponential with mean biologic half-life (T1/2b) of 1.95 h, while blood clearance was bi-exponential with mean T1/2b of 0.3 h (58 %) for the rapid α phase and 6.1 h (42%) for the slower β phase. Urinary bladder received the highest radiation dose with a mean absorbed dose of 0.186 ± 0.195 mGy/MBq. Mean total body dose was 0.011 ± 0.011 mGy/MBq and the effective dose was 0.023± 0.012 mSv/Mbq. Both skeletal and soft tissue lesions were visualized with high contrast. The maximum standard uptake value (SUVMAX) [mean ± standard deviation (SD)] of lesions at 1-2 h p.i. was 8.6 ± 9.6. Conclusion: Preliminary data show that (18)F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. PET imaging with (18)F-MFBG allows for same-day imaging of NETs. (18)F-MFBG appears highly promising for imaging of patients with NETs, especially children with neuroblastoma.

PMID: 28705916 [PubMed - as supplied by publisher]