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6. Biodistribution and dosimetry of the PET radioligand [18F]CHDI-650 in mice for detection of mutant huntingtin aggregates.

Author

Akkermans, Jordy, Miranda, Alan, Verhaeghe, Jeroen, Elvas, Filipe, Zajicek, Franziska, Bard, Jonathan, Liu, Longbin, Khetarpal, Vinod, Doot, Robert, Staelens, Steven, and Bertoglio, Daniele

Subjects
HUNTINGTON disease, POSITRON emission tomography, TRINUCLEOTIDE repeats, MEDICAL dosimetry, HUNTINGTIN protein
Abstract

Background: Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene which encodes the mutant huntingtin protein (mHTT) that is associated with HD-related neuropathophysiology. Noninvasive visualization of mHTT aggregates in the brain, with positron emission tomography (PET), will allow to reliably evaluate the efficacy of therapeutic interventions in HD. This study aimed to assess the radiation burden of [18F]CHDI-650, a novel fluorinated mHTT radioligand, in humans based on both in vivo and ex vivo biodistribution in mice and subsequent determination of dosimetry for dosing in humans. Results: Wild-type male and female CD-1 Swiss mice (n = 15/sex) were used to assess in vivo PET imaging-based and ex vivo biodistribution-based tracer distribution of [18F]CHDI-650 at 30-, 60-, 120-, 240- and 360-min post-injection. Three-dimensional volumes of interest of the organs were drawn on the co-registered PET/CT image and organs were collected after dissection. Organ radioactivity levels were determined using both modalities. The residence time was calculated and extrapolated to human phantoms. The absorbed and effective doses were computed with OLINDA/EXM 2.2 and IDAC-Dose2.1. Ex vivo and PET-imaging biodistribution of [18F]CHDI-650 showed rapid washout after 30 min in most of the organs with the highest uptake in the gallbladder and urine in mice. Extrapolation of the data to human phantoms with OLINDA showed a total mean in vivo based effective dose of 21.7 μSv/MBq with the highest equivalent organ dose in the urinary bladder wall (4.52 μSv/MBq). The total mean ex vivo based effective dose was calculated to be 20.6 μSv/MBq. The highest equivalent organ dose ex vivo in the urinary bladder wall was estimated to be 4.22 μSv/MBq. The predicted exposure in humans using IDAC-Dose correlated well to those obtained with OLINDA for both in vivo and ex vivo measurements (r = 0.9320 and r = 0.9368, respectively). Conclusions: Dosimetry analysis indicated absorbed and effective doses of [18F]CHDI-650 are well below the recommended limits, suggesting that the radioligand is suitable for clinical assessment. Based on the highest effective dose estimates, an injection of 370 MBq in humans would result in a radiation dose of 8.03 mSv. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Preclinical evaluation of the novel [18F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington's disease.

Author

Zajicek, Franziska, Verhaeghe, Jeroen, De Lombaerde, Stef, Van Eetveldt, Annemie, Miranda, Alan, Munoz-Sanjuan, Ignacio, Dominguez, Celia, Khetarpal, Vinod, Bard, Jonathan, Liu, Longbin, Staelens, Steven, and Bertoglio, Daniele

Subjects
HUNTINGTON disease, POSITRON emission tomography, AUTORADIOGRAPHY, LABORATORY mice, RADIOACTIVE tracers, ANIMAL disease models
Abstract

Purpose: Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington's disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. Methods: After characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand. Results: Plasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p < 0.0001) despite the poor test–retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R. Conclusion: Overall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway. [ABSTRACT FROM AUTHOR]

Published
2024
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22. State-associated changes in longitudinal [18F]-PBR111 TSPO PET imaging of psychosis patients: Evidence for the accelerated ageing hypothesis?

Author

De Picker, Livia, Ottoy, Julie, Verhaeghe, Jeroen, Deleye, Steven, wyffels, Leonie, Fransen, Erik, Kosten, Lauren, Sabbe, Bernard, Coppens, Violette, Timmers, Maarten, de Boer, Peter, Van Nueten, Luc, Op De Beeck, Ken, Oberacher, Herbert, Vanhoenacker, Filip, Ceyssens, Sarah, Stroobants, Sigrid, Staelens, Steven, and Morrens, Manuel

Published
2019
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28. In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using11C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease

Author

Bertoglio, Daniele, primary, Weiss, Alison R., additional, Liguore, William, additional, Martin, Lauren Drew, additional, Hobbs, Theodore, additional, Templon, John, additional, Srinivasan, Sathya, additional, Dominguez, Celia, additional, Munoz-Sanjuan, Ignacio, additional, Khetarpal, Vinod, additional, Verhaeghe, Jeroen, additional, Staelens, Steven, additional, Link, Jeanne, additional, Liu, Longbin, additional, Bard, Jonathan A., additional, and McBride, Jodi L., additional

Published
2023
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43. Accurate image derived input function in [18F]SynVesT-1 mouse studies using isoflurane and ketamine/xylazine anesthesia.

Author

Miranda, Alan, Bertoglio, Daniele, Staelens, Steven, and Verhaeghe, Jeroen

Subjects
ISOFLURANE, POSITRON emission tomography, MATRIX decomposition, NONNEGATIVE matrices, XYLAZINE, KETAMINE
Abstract

Background: Kinetic modeling in positron emission tomography (PET) requires measurement of the tracer plasma activity in the absence of a suitable reference region. To avoid invasive blood sampling, the use of an image derived input function has been proposed. However, an accurate delineation of the blood pool region in the PET image is necessary to obtain unbiased blood activity. Here, to perform brain kinetic modeling in [18F]SynVesT-1 dynamic scans, we make use of non-negative matrix factorization (NMF) to unmix the activity signal from the different tissues that can contribute to the heart region activity, and extract only the left ventricle activity in an unbiased way. This method was implemented in dynamic [18F]SynVesT-1 scans of mice anesthetized with either isoflurane or ketamine–xylazine, two anesthestics that we showed to affect differently radiotracer kinetics. The left ventricle activity (NMF-IDIF) and a manually delineated cardiac activity (IDIF) were compared with arterial blood samples (ABS), and for isoflurane anesthetized mice, arteriovenous (AV) shunt blood data were compared as well. Finally, brain regional 2 tissue compartment modeling was performed using IDIF and NMF-IDIF, and the model fit accuracy (weighted symmetrical mean absolute percentage error, wsMAPE) as well as the total volume of distribution (VT) were compared. Results: In isoflurane anesthetized mice, the difference between ABS and NMF-IDIF activity (+ 12.8 ± 11%, p = 0.0023) was smaller than with IDIF (+ 16.4 ± 9.8%, p = 0.0008). For ketamine–xylazine anesthetized mice the reduction in difference was larger (NMF-IDIF: 16.9 ± 10%, p = 0.0057, IDIF: 56.3 ± 14%, p < 0.0001). Correlation coefficient between isoflurane AV-shunt time activity curves and NMF-IDIF (0.97 ± 0.01) was higher than with IDIF (0.94 ± 0.03). The brain regional 2TCM wsMAPE was improved using NMF-IDIF compared with IDIF, in isoflurane (NMF-IDIF: 1.24 ± 0.24%, IDIF: 1.56 ± 0.30%) and ketamine–xylazine (NMF-IDIF: 1.40 ± 0.24, IDIF: 2.62 ± 0.27) anesthetized mice. Finally, brain VT was significantly (p < 0.0001) higher using NMF-IDIF compared with IDIF, in isoflurane (3.97 ± 0.13% higher) and ketamine–xylazine (32.7 ± 2.4% higher) anesthetized mice. Conclusions: Image derived left ventricle blood activity calculated with NMF improves absolute activity quantification, and reduces the error in the kinetic modeling fit. These improvements are more pronounced in ketamine–xylazine than in isoflurane anesthetized mice. [ABSTRACT FROM AUTHOR]

Published
2023
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