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Article ; Online: A roadmap for sole Cherenkov radiators with SiPMs in TOF-PET.

Kratochwil, Nicolaus / Gundacker, Stefan / Auffray, Etiennette

2021 Volume 66, Issue 19

Abstract: Time of flight positron emission tomography can strongly benefit from a very accurate time estimator given by Cherenkov radiation, which is produced upon a 511 keV positron-electron annihilation gamma interaction in heavy inorganic scintillators. While ... ...

Abstract	Time of flight positron emission tomography can strongly benefit from a very accurate time estimator given by Cherenkov radiation, which is produced upon a 511 keV positron-electron annihilation gamma interaction in heavy inorganic scintillators. While time resolution in the order of 30 ps full width at half maximum (FWHM) has been reported using MCP-PMTs and black painted Cherenkov radiators, such solutions have several disadvantages, like high cost and low detection efficiency of nowadays available MCP-PMTs. On the other hand, silicon photomultipliers (SiPMs) are not limited by those obstacles and provide high photon detection efficiency with a decent time response. Timing performance of PbF
Language	English
Publishing date	2021-09-21
Publishing country	England
Document type	Journal Article
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ac212a
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Article ; Online: Pushing Cherenkov PET with BGO via coincidence time resolution classification and correction.

Kratochwil, Nicolaus / Gundacker, Stefan / Lecoq, Paul / Auffray, Etiennette

Physics in medicine and biology

2020 Volume 65, Issue 11, Page(s) 115004

Abstract: Bismuth germanate (BGO) shows good properties for positron emission tomography (PET) applications, but was substituted by the development of faster crystals like lutetium oxyorthosilicate (LSO) for time-of-flight PET (TOF-PET). Recent improvements in ... ...

Abstract	Bismuth germanate (BGO) shows good properties for positron emission tomography (PET) applications, but was substituted by the development of faster crystals like lutetium oxyorthosilicate (LSO) for time-of-flight PET (TOF-PET). Recent improvements in silicon photomultipliers (SiPMs) and fast readout electronics make it possible to access the Cherenkov photon signal produced upon 511 keV interaction, which makes BGO a cost-effective candidate for TOF-PET. Tails in the time-delay distribution, however, remain a challenge. These are mainly caused by the high statistical fluctuation on the Cherenkov photons detected. To select fast events with a high detected Cherenkov photon number, the signal rise time of the SiPM was used for discrimination. The charge, time delay and signal rise time was measured for two different lengths of BGO crystals coupled to FBK NUV-HD SiPMs and high frequency readout in a coincidence time resolution setup. The recorded events were divided into 5 × 5 categories based on the signal rise time, and time resolutions of 200 ± 3 ps for 2 × 2 × 20 mm
MeSH term(s)	Bismuth ; Electronics ; Germanium ; Image Processing, Computer-Assisted/methods ; Lutetium ; Photons ; Positron-Emission Tomography/methods ; Scintillation Counting/instrumentation ; Scintillation Counting/methods ; Silicates
Chemical Substances	Silicates ; lutetium orthosilicate ; Germanium (00072J7XWS) ; bismuth germanium oxide (12233-56-6) ; Lutetium (5H0DOZ21UJ) ; Bismuth (U015TT5I8H)
Language	English
Publishing date	2020-06-05
Publishing country	England
Document type	Journal Article
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ab87f9
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Article ; Online: Advances in heterostructured scintillators: toward a new generation of detectors for TOF-PET.

Pagano, Fiammetta / Kratochwil, Nicolaus / Salomoni, Matteo / Pizzichemi, Marco / Paganoni, Marco / Auffray, Etiennette

Physics in medicine and biology

2022 Volume 67, Issue 13

Abstract: Objective. ...

Abstract	Objective.
MeSH term(s)	Computer Simulation ; Humans ; Photons ; Plastics ; Positron-Emission Tomography/methods ; Scintillation Counting/methods
Chemical Substances	Plastics
Language	English
Publishing date	2022-06-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ac72ee
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Article ; Online: Performance evaluation of the FastIC readout ASIC with emphasis on Cherenkov emission in TOF-PET.

Piller, Markus / Castilla, Antonio M / Terragni, Giulia / Alozy, Jerome / Auffray, Etiennette / Ballabriga, Rafael / Campbell, Michael / Deutschmann, Bernd / Gascon, David / Gola, Alberto / Merzi, Stefano / Michalowska-Forsyth, Alicja / Penna, Michele / Fernández, Sergio Gómez / Kratochwil, Nicolaus

Physics in medicine and biology

2024

Abstract: Objective: The efficient usage of prompt photons like Cherenkov emission is of great interest for the design of the next generation, cost-effective, and ultrahigh-sensitivity TOF-PET scanners. With custom, high power consuming, readout electronics and ... ...

Abstract	Objective: The efficient usage of prompt photons like Cherenkov emission is of great interest for the design of the next generation, cost-effective, and ultrahigh-sensitivity TOF-PET scanners. With custom, high power consuming, readout electronics and fast digitization the prospect of sub-300 ps FWHM with PET-sized BGO crystals have been shown. However, these results are not scalable to a full system consisting of thousands of detector elements. Approach. To pave the way toward a full TOF-PET scanner, we examine the performance of the FastIC ASIC with Cherenkov-emitting scintillators (BGO), together with one of the most recent SiPM detector developments based on metal trenching from FBK. The FastIC is a highly configurable ASIC with 8 input channels, a power consumption of 12 mW/ch and excellent linearity on the energy measurement. To put the timing performance of the FastIC into perspective, comparison measurements with high-power consuming readout electronics are performed. Main results. We achieve a best CTR FWHM of 330 ps for 2x2x3 mm3 and 490 ps for 2x2x20 mm3 BGO crystals with the FastIC. In addition, using 20 mm long LSO:CeCa crystals, CTR values of 129 ps FWHM have been measured with the FastIC, only slightly worse to the state-of-the-art of 95 ps obtained with discrete HF electronics. Significance. For the first time, the timing capability of BGO with a scalable ASIC has been evaluated. The findings underscore the potential of the FastIC ASIC in the development of cost-effective TOF-PET scanners with excellent timing characteristics.
Language	English
Publishing date	2024-04-24
Publishing country	England
Document type	Journal Article
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ad42fe
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Article ; Online: Simplifying the Execution of HepatoPac MetID Experiments: Metabolite Profile and Intrinsic Clearance Comparisons.

Ballard, T Eric / Kratochwil, N / Cox, Loretta M / Moen, Mark A / Klammers, F / Ekiciler, A / Goetschi, A / Walter, I

Drug metabolism and disposition: the biological fate of chemicals

2020 Volume 48, Issue 9, Page(s) 804–810

Abstract: The HepatoPac micropatterned coculture (MPCC) hepatocyte system has been shown to be an effective tool to investigate the qualitative human and preclinical species' metabolite profiles of new drug candidates. However, additional improvements to the ... ...

Abstract	The HepatoPac micropatterned coculture (MPCC) hepatocyte system has been shown to be an effective tool to investigate the qualitative human and preclinical species' metabolite profiles of new drug candidates. However, additional improvements to the overall study conditions and execution, layout, and human-donor count could be made. To that end, we have evaluated several ways to increase the amount of data one can generate per MPCC plate and how to more efficiently execute a MPCC study for the purpose of metabolite generation. Herein, we compare a set of compounds using single- and 10-donor pooled human MPCC hepatocytes. Intrinsic clearance and mean metabolic activities assessed by diverse enzyme markers were comparable between the single- and 10-donor pool. We have confirmed that the generated metabolite profiles were indistinguishable between the single- and 10-donor pool and also that rat MPCC can be performed at 400 µl media volume, which greatly simplifies study execution. Additional tips for successful study execution are also described. SIGNIFICANCE STATEMENT: When using the HepatoPac micropatterned coculture (MPCC) system, sometimes simple experimental condition variables or problematic plate designs can hamper productive study execution. We evaluated conditions to increase the amount of data one can generate per MPCC plate and, perhaps more importantly, execute that study more efficiently with less likelihood of error. We describe some of our key learnings, provide an examination of enzyme activity levels and clearance values, and provide some recommendations to simplify the execution of a HepatoPac experiment.
MeSH term(s)	Animals ; Biotransformation ; Chromatography, High Pressure Liquid/methods ; Coculture Techniques/methods ; Datasets as Topic ; Drug Evaluation, Preclinical/methods ; Female ; Fibroblasts ; Hepatobiliary Elimination ; Hepatocytes/metabolism ; Humans ; Male ; Metabolomics/methods ; Primary Cell Culture/methods ; Rats ; Tandem Mass Spectrometry/methods
Language	English
Publishing date	2020-07-04
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.120.000013
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Article: Image Reconstruction Analysis for Positron Emission Tomography With Heterostructured Scintillators.

Mohr, Philipp / Efthimiou, Nikos / Pagano, Fiammetta / Kratochwil, Nicolaus / Pizzichemi, Marco / Tsoumpas, Charalampos / Auffray, Etiennette / Ziemons, Karl

IEEE transactions on radiation and plasma medical sciences

2022 Volume 7, Issue 1, Page(s) 41–51

Abstract: The concept ... ...

Abstract	The concept of
Language	English
Publishing date	2022-09-22
Publishing country	United States
Document type	Journal Article
ISSN	2469-7311
ISSN	2469-7311
DOI	10.1109/trpms.2022.3208615
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Article: TOF-PET Image Reconstruction With Multiple Timing Kernels Applied on Cherenkov Radiation in BGO.

Efthimiou, Nikos / Kratochwil, Nicolaus / Gundacker, Stefan / Polesel, Andrea / Salomoni, Matteo / Auffray, Etiennette / Pizzichemi, Marco

IEEE transactions on radiation and plasma medical sciences

2020 Volume 5, Issue 5, Page(s) 703–711

Abstract: Today Time-of-Flight (TOF), in PET scanners, assumes a single, well-defined timing resolution for all events. However, recent BGO-Cherenkov detectors, combining prompt Cherenkov emission and the typical BGO scintillation, can sort events into multiple ... ...

Abstract	Today Time-of-Flight (TOF), in PET scanners, assumes a single, well-defined timing resolution for all events. However, recent BGO-Cherenkov detectors, combining prompt Cherenkov emission and the typical BGO scintillation, can sort events into multiple timing kernels, best described by the Gaussian mixture models. The number of Cherenkov photons detected per event impacts directly the detector time resolution and signal rise time, which can later be used to improve the coincidence timing resolution. This work presents a simulation toolkit which applies multiple timing spreads on the coincident events and an image reconstruction that incorporates this information. A full cylindrical BGO-Cherenkov PET model was compared, in terms of contrast recovery and contrast-to-noise ratio, against an LYSO model with a time resolution of 213 ps. Two reconstruction approaches for the mixture kernels were tested: 1) mixture Gaussian and 2) decomposed simple Gaussian kernels. The decomposed model used the exact mixture component applied during the simulation. Images reconstructed using mixture kernels provided similar mean value and less noise than the decomposed. However, typically, more iterations were needed. Similarly, the LYSO model, with a single TOF kernel, converged faster than the BGO-Cherenkov with multiple kernels. The results indicate that the model complexity slows down convergence. However, due to the higher sensitivity, the contrast-to-noise ratio was 26.4% better for the BGO model.
Language	English
Publishing date	2020-12-31
Publishing country	United States
Document type	Journal Article
ISSN	2469-7311
ISSN	2469-7311
DOI	10.1109/trpms.2020.3048642
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Article ; Online: Experimental time resolution limits of modern SiPMs and TOF-PET detectors exploring different scintillators and Cherenkov emission.

Gundacker, Stefan / Martinez Turtos, Rosana / Kratochwil, Nicolaus / Pots, Rosalinde Hendrika / Paganoni, Marco / Lecoq, Paul / Auffray, Etiennette

Physics in medicine and biology

2020 Volume 65, Issue 2, Page(s) 25001

Abstract: Solid state photodetectors like silicon photomultipliers (SiPMs) are playing an important role in several fields of medical imaging, life sciences and high energy physics. They are able to sense optical photons with a single photon detection time ... ...

Abstract	Solid state photodetectors like silicon photomultipliers (SiPMs) are playing an important role in several fields of medical imaging, life sciences and high energy physics. They are able to sense optical photons with a single photon detection time precision below 100 ps, making them ideal candidates to read the photons generated by fast scintillators in time of flight positron emission tomography (TOF-PET). By implementing novel high-frequency readout electronics, it is possible to perform a completely new evaluation of the best timing performance achievable with state-of-the-art analog-SiPMs and scintillation materials. The intrinsic SiPM single photon time resolution (SPTR) was measured with Ketek, HPK, FBK, SensL and Broadcom devices. Also, the best achieved coincidence time resolution (CTR) for these devices was measured with LSO:Ce:Ca of [Formula: see text] mm
MeSH term(s)	Bismuth ; Germanium ; Monte Carlo Method ; Photons ; Positron-Emission Tomography/instrumentation ; Scintillation Counting/instrumentation ; Silicon ; Time Factors
Chemical Substances	Germanium (00072J7XWS) ; bismuth germanium oxide (12233-56-6) ; Bismuth (U015TT5I8H) ; Silicon (Z4152N8IUI)
Language	English
Publishing date	2020-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ab63b4
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Article ; Online: Addressing Today's Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of the

Fowler, Stephen / Brink, Andreas / Cleary, Yumi / Günther, Andreas / Heinig, Katja / Husser, Christophe / Kletzl, Heidemarie / Kratochwil, Nicole / Mueller, Lutz / Savage, Mark / Stillhart, Cordula / Tuerck, Dietrich / Ullah, Mohammed / Umehara, Kenichi / Poirier, Agnès

Drug metabolism and disposition: the biological fate of chemicals

2021 Volume 50, Issue 1, Page(s) 65–75

Abstract: Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to ... ...

Abstract	Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro-in vivo-in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development. Risdiplam (Evrysdi)-an orally bioavailable, small molecule approved by the US Food and Drug Administration and more recently by the European Medicines Agency for the treatment of patients ≥2 months of age with spinal muscular atrophy-is presented here as a case study. Risdiplam is a low-turnover compound whose metabolism is mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges of risdiplam are discussed: predicting in vivo hepatic clearance, determining in vitro metabolites with regard to metabolites in safety testing guidelines, elucidating enzymes responsible for clearance, and estimating potential drug-drug interactions. A combination of in vitro and in vivo results was successfully extrapolated and used to develop a robust physiologically based pharmacokinetic model of risdiplam. These results were verified through early clinical studies, further strengthening the understanding of the ADME properties of risdiplam in humans. These approaches can be applied to other compounds with similar ADME profiles, which may be difficult to investigate using standard methods. SIGNIFICANCE STATEMENT: Risdiplam is the first approved, small-molecule,
MeSH term(s)	Animals ; Azo Compounds/metabolism ; Azo Compounds/pharmacokinetics ; Humans ; In Vitro Techniques ; Pharmaceutical Preparations/metabolism ; Pyrimidines/metabolism ; Pyrimidines/pharmacokinetics ; RNA Splicing/drug effects ; RNA, Messenger/metabolism ; Survival of Motor Neuron 2 Protein/metabolism ; Tissue Distribution
Chemical Substances	Azo Compounds ; Pharmaceutical Preparations ; Pyrimidines ; RNA, Messenger ; SMN2 protein, human ; Survival of Motor Neuron 2 Protein ; Risdiplam (76RS4S2ET1)
Language	English
Publishing date	2021-10-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.121.000563
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Article ; Online: Bioanalytics and pharmacokinetics of the nociceptin/orphanin FQ peptide receptor agonist RO0646198 in Wistar rats and Cynomolgus monkeys.

Heinig, Katja / Kratochwil, Nicole / Bucheli, Franz / Thomae, Anita

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

2010 Volume 878, Issue 23, Page(s) 2101–2105

Abstract: This manuscript describes the determination of the nociceptin/orphanin FQ peptide (NOP) receptor agonist RO0646198 in rat and Cynomolgus monkey plasma using liquid chromatography coupled to tandem mass spectrometry. The structural analogue RO0658791 ... ...

Abstract	This manuscript describes the determination of the nociceptin/orphanin FQ peptide (NOP) receptor agonist RO0646198 in rat and Cynomolgus monkey plasma using liquid chromatography coupled to tandem mass spectrometry. The structural analogue RO0658791 served as internal standard. After protein precipitation with ethanol, clean up and enrichment was carried out by on-line solid-phase extraction on a 10mm C18 trapping column. Gradient separation was performed on a 50 mm C18 analytical column, followed by electrospray ionization and detection in positive ion selected reaction monitoring (SRM) mode. The total run time was 2.5 min. The lower limit of quantification (LLOQ) was 10 pg/mL. Precisions were below 19% and accuracies were between 86% and 118%. The recoveries were above 90%, and no significant matrix effect was observed. The method was successfully applied to low dose pharmacokinetic studies. The bioavailability after oral dosing was below 5% for rats and below 1% in Cynomolgus monkeys, limiting the application of RO0646198 in the clinic to parenteral routes.
MeSH term(s)	Animals ; Drug Administration Routes ; Humans ; Imidazoles/administration & dosage ; Imidazoles/blood ; Imidazoles/pharmacokinetics ; Imidazoles/pharmacology ; Macaca fascicularis/blood ; Rats ; Rats, Wistar ; Receptors, Opioid/agonists ; Reference Standards ; Spectrometry, Mass, Electrospray Ionization/methods ; Spiro Compounds/administration & dosage ; Spiro Compounds/blood ; Spiro Compounds/pharmacokinetics ; Spiro Compounds/pharmacology ; Time Factors
Chemical Substances	Imidazoles ; Receptors, Opioid ; Ro 64-6198 ; Spiro Compounds ; nociceptin receptor
Language	English
Publishing date	2010-08-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1180823-8
ISSN	1873-376X ; 0378-4347 ; 1570-0232 ; 1387-2273
ISSN (online)	1873-376X
ISSN	0378-4347 ; 1570-0232 ; 1387-2273
DOI	10.1016/j.jchromb.2010.06.013
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