Quantitative in vivo 23Na MR imaging of the healthy human kidney: determination of physiological ranges at 3.0T with comparison to DWI and BOLD

2013 ◽  
Vol 26 (6) ◽  
pp. 501-509 ◽  
Author(s):  
Stefan Haneder ◽  
Paul Kettnaker ◽  
Simon Konstandin ◽  
John N. Morelli ◽  
Lothar R. Schad ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Human Kidney ◽  
Healthy Human

scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

scholarly journals In Vivo Determination of Bone Structure in Postmenopausal Women: A Comparison of HR-pQCT and High-Field MR Imaging

2007 ◽  
Vol 23 (4) ◽  
pp. 463-474 ◽  
Author(s):  
Galateia J Kazakia ◽  
Benedict Hyun ◽  
Andrew J Burghardt ◽  
Roland Krug ◽  
David C Newitt ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Postmenopausal Women ◽  
High Field ◽  
Bone Structure ◽  
High Field Mr

scholarly journals Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy

2020 ◽  
Author(s):  
Eline A. M. Ruigrok ◽  
Nicole van Vliet ◽  
Simone U. Dalm ◽  
Erik de Blois ◽  
Dik C. van Gent ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radionuclide Therapy ◽  
Specific Binding ◽  
Human Kidney ◽  
Careful Evaluation ◽  
Healthy Human ◽  
Binding Characteristics ◽  
Preclinical Evaluation

Abstract Purpose Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion [177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.

Deuterium MR in Vivo Imaging of the Rat Eye Using 2H2O

1995 ◽  
Vol 36 (4-6) ◽  
pp. 552-555 ◽  
Author(s):  
T. Obata ◽  
H. Ikehira ◽  
F. Shishido ◽  
N. Fukuda ◽  
Y. Ueshima ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Water Movement ◽  
Pulse Sequence ◽  
Signal To Noise Ratio ◽  
Spin Echo ◽  
Dynamic Change ◽  
Intraperitoneal Administration ◽  
Compartment Model

In vivo euterium MR imaging (2H MR) was investigated in rats after intraperitoneal administration of deuterated saline, and a dynamic study of the water movement in rat eyes was performed. Deuterium MR imaging was carried out by means of a gradient-echo (GRE) and a spin-echo (SE) pulse sequence. The rat eye was imaged in 2H MR more selectively by SE than by GRE, but a lower signal-to-noise ratio was obtained in 2H MR imaging using the SE sequence. The MR signal intensity of the rat eye was followed by a 3-compartment model, which enabled determination of the flow rate constant of the water in the eye (0.359/min). Deuterium MR imaging is useful to visualize the dynamic change of water in rat eyes using 2H MR at the same magnetic field (2 T) that can also be used for conventional MR imaging in humans.

scholarly journals Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

2014 ◽  
Vol 34 (6) ◽  
pp. 989-994 ◽  
Author(s):  
David R Owen ◽  
Qi Guo ◽  
Nicola J Kalk ◽  
Alessandro Colasanti ◽  
Dimitra Kalogiannopoulou ◽  
...  
Keyword(s):  
Volume Of Distribution ◽  
Translocator Protein ◽  
Binding Potential ◽  
Healthy Human ◽  
Positron Emission ◽  
Dose Dependent ◽  
In Vitro Data

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential ( BP ND). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution ( V ND), and hence estimate the BP ND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution ( V T) of MABs (2.94 ± 0.31) was lower than V T of HABs (4.33 ± 0.29) ( P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

Iron sucrose (“rbt-3”) activates the hepatic and renal hamp1 gene, evoking renal hepcidin loading and resistance to cisplatin nephrotoxicity

2020 ◽  
Author(s):  
Richard A Zager ◽  
Ali C M Johnson ◽  
Renibus Therapeutics
Keyword(s):  
Human Kidney ◽  
Time Lapse ◽  
Healthy Human ◽  
Protein Levels ◽  
Cisplatin Nephrotoxicity ◽  
Human Volunteers ◽  
Nrf2 Activation ◽  
Plasma And Urine Samples

Abstract Background Fe sucrose (FeS) administration induces a state of renal preconditioning, protecting against selected forms of AKI. Recent evidence suggests that recombinant hepcidin also mitigates acute renal damage. Hence, the goals of this study were as follows: i) Determine whether a new proprietary FeS formulation (“RBT-3”), can acutely activate the hepcidin (HAMP1) gene in humans, raising plasma and renal hepcidin concentrations; ii) assess whether the kidney participates in this posited RBT-3-hepcidin generation response; iii) test whether RBT-3 can mitigate a clinically relevant AKI model (experimental cisplatin toxicity); and iv) explore whether mechanisms in addition to hepcidin generation are operative in RBT-3’s cytoprotective effects. Methods Healthy human volunteers (n, 9) and subjects with stage 3-4 CKD (n, 9) received 120, 240, or 360 mg of RBT-3 (IV over 2 hrs). Plasma and urine samples were collected and assayed for hepcidin levels (0-72 hrs post RBT-3 injection). In complementary mouse experiments, RBT-3 effects on hepatic vs. renal hepcidin (HAMP1) mRNA and protein levels were compared. RBT-3’s impact on the mouse Nrf2 pathway, and on experimental cisplatin nephrotoxicity, were assessed. Direct effects of exogenous hepcidin on in vivo and in vitro (HK-2 cells) cisplatin toxicity were also tested. Results RBT-3 induced rapid, dose dependent, and comparable plasma hepcidin increases in both HVs and CKD subjects (∼15x baseline within 24 hrs). Human kidney hepcidin exposure was confirmed by 4 fold urinary hepcidin increases. RBT-3 up-regulated mouse hepcidin mRNA, but much more so in kidney (&gt;25x) vs. liver (∼2x). RBT-3 also activated kidney Nrf2 (increased Nrf2 nuclear binding; increased Nrf2-responsive gene mRNAs: HO-1, SrXN1, GCLC, NQO1). RBT-3 preconditioning (18 hr time lapse) markedly attenuated experimental cisplatin nephrotoxicity (∼50% BUN/creatinine decrements), in part, by reducing renal cisplatin uptake by 40%. Exogenous hepcidin (without RBT-3) treatment conferred protection against mild in vivo (but not in vitro) cisplatin toxicity. Conclusions RBT-3 acutely and dramatically up-regulates cytoprotective hepcidin production, increasing renal hepcidin levels. However, additional cytoprotective mechanisms are activated by RBT-3 (e.g., Nrf2 activation; reduced cisplatin uptake). Thus, RBT-3-induced preconditioning likely confers renal resistance to cisplatin via an interplay of multiple cytoprotective activities.

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

Storage of Human Blood Platelets

1974 ◽  
Vol 32 (02/03) ◽  
pp. 405-416 ◽  
Author(s):  
M. R Hardeman ◽  
Carina J L. Heynens
Keyword(s):  
Storage Temperature ◽  
Platelet Rich Plasma ◽  
Blood Platelets ◽  
Storage Period ◽  
Serotonin Uptake ◽  
Hypotonic Shock ◽  
Glycolytic Intermediates

SummaryStorage experiments were performed at 4°, 25° and 37° C with platelet-rich plasma under sterile conditions. In some experiments also the effect of storing platelets at 4° C in whole blood was investigated.Before, during and after three days of storage, the platelets were tested at 37° C for their serotonin uptake and response to hypotonic shock. In addition some glycolytic intermediates were determined.A fair correlation was noticed between the serotonin uptake and hypotonic shock experiments. Both parameters were best maintained at 25° C. Also platelet counting, performed after the storage period, indicated 25° C as the best storage temperature. Determination of glycolytic intermediates did not justify any conclusion regarding the optimal storage temperature. Of the various anticoagulants studied, ACD and heparin gave the best results as to the serotonin uptake and hypotonic shock response, either with fresh or stored platelets. The use of EDTA resulted in the lowest activity, especially after storage.The results of these storage experiments in vitro, correspond well with those in vivo reported in the literature.

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