Dataset Information

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.

ABSTRACT:

Purpose

As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington's disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [¹¹C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.

Methods

After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [³H]CHDI-626 autoradiography.

Results

Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [³H]CHDI-626 autoradiography.

Conclusion

With clinical evaluation underway, [¹¹C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

SUBMITTER: Bertoglio D

PROVIDER: S-EPMC8921134 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.

Bertoglio Daniele D Verhaeghe Jeroen J Miranda Alan A Wyffels Leonie L Stroobants Sigrid S Mrzljak Ladislav L Khetarpal Vinod V Skinbjerg Mette M Liu Longbin L Dominguez Celia C Munoz-Sanjuan Ignacio I Bard Jonathan J Staelens Steven S

European journal of nuclear medicine and molecular imaging 20211015 4

<h4>Purpose</h4>As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington's disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [<sup>11</sup>C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.<h4>Methods</h4>After evaluating radi ...[more]

PMID: 34651228

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Project description:BackgroundHuntington'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.ResultsWild-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).ConclusionsDosimetry 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.

Dataset Information

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.

Purpose

Methods

Results

Conclusion

Publications

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.

Similar Datasets

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