A Phase 1 Positron Emission Tomography Study to Measure Cholesterol 24S-Hydroxylase Target Occupancy of TAK-935

The drug being tested in this study is called TAK-935. TAK-935 is being tested to examine the degree and duration of brain CH24H enzyme occupancy/target engagement as a function of TAK-935 plasma concentration in order to guide dosing and schedule for future clinical trials with TAK-935. This study will utilize the PET ligand \[18F\]MNI-792 to evaluate the brain CH24H occupancy of TAK-935 after single dose oral administration in healthy adult participants. The study will evaluate up to 16 participants. The first 2 participants will take TAK-935 600 mg oral solution and undergo PET imaging using tracer \[18F\]MNI-792 up to 5 mcg (up to 370 MBq), injection, intravenously prior to each PET scan at Baseline, 45 minutes and 10 hours post-TAK-935 dose. TAK-935 dose and timing of post-dose scans for subsequent participants will be based on the data from the previous participants. This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 55 days. Participants will make 4 visits to the clinic, including 2 confinement periods to the clinic for PET imaging. Participants will be contacted by phone on Day 28 for follow-up safety assessments.

• TAK-935 (Drug): TAK-935 oral solution.
• [18F]MNI-792 (tracer) (Drug): \[18F\]MNI-792 injection.

Primary outcomes

• Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 45 Minutes Post-TAK-935 Dose [45 minutes post-TAK-935 dose]: CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: total volume of distribution \[VT\] (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT \[Baseline\] - non-displaceable volume of distribution \[VND\]), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 45 minutes post-TAK-935 dose.
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 2 Hours Post-TAK-935 Dose [2 hours post-TAK-935 dose]: CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 10 Hours Post-TAK-935 Dose [10 hours post-TAK-935 dose]: CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 10 hour post-TAK-935 dose.
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 24 Hours Post-TAK-935 Dose [24 hours post-TAK-935 dose]: CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.

Secondary outcomes

• Plasma Concentration of TAK-935 During Post-TAK-935 Dosing PET Scan Periods [At time 0 (just after tracer injection), 1 hour after tracer injection and 2 hours after tracer injection for each post-TAK-935 dosing PET scan period]
• Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) [Baseline (Day -1): 1 hour and at multiple timepoints (up to 12 hours) post check in and Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-TAK-935 dose]: Percent change was calculated as = \[(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)\]*100 percent.

Sex: All, ages: 19 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

1. In the opinion of the investigator, is capable of understanding and complying with protocol requirements.
2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations.
3. Is a healthy male or female and aged 19 to 55 years, inclusive, at the time of informed consent and first study medication dose.
4. Weighs at least 45 kilogram (kg) and has a body mass index (BMI) from 18.0 to 30.0 kilogram per square meter (kg/m\^2), inclusive at Screening.
5. A female of non-bearing potential (example post-menopausal by history; or history of hysterectomy, bilateral salpingectomy, or oophorectomy).

Exclusion Criteria:

1. Have a known history or evidence of a clinically significant disorder (including neurologic and psychiatric), or disease that in the opinion of the study investigator would pose a risk to the participant safety or interfere with the study evaluation, procedures or completion.
2. Contraindication to magnetic resonance imaging (MRI) based on the standard MRI radiography screening questionnaire.
3. Had exposure to any radiation greater than (>) 15 millisievert (mSv)/year (example, occupational or radiation therapy) within the previous year prior to Baseline imaging.
4. Has a known hypersensitivity to any component of the formulation of TAK-935 or related compounds, or to \[18F\]MNI-792 or to any of its components.
5. Clinically significant abnormal findings on brain MRI scan or findings on brain MRI that may interfere with the interpretation of the PET imaging.
6. Use of any over-the-counter, herbal, or prescription medications or supplements within 30 days prior to baseline imaging.

Participant flow

Outcome results

• Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 45 Minutes Post-TAK-935 Dose (Primary), Number, percentage of occupancy: TAK-935 600 mg NA
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 2 Hours Post-TAK-935 Dose (Primary), Number, percentage of occupancy: TAK-935 50 mg 70; TAK-935 100 mg 79; TAK-935 200 mg 96; TAK-935 300 mg 91; TAK-935 600 mg NA
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 10 Hours Post-TAK-935 Dose (Primary), Number, percentage of occupancy: TAK-935 600 mg 92
• CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 24 Hours Post-TAK-935 Dose (Primary), Number, percentage of occupancy: TAK-935 50 mg 22; TAK-935 100 mg 13; TAK-935 200 mg 79; TAK-935 300 mg 46; TAK-935 600 mg NA
• Plasma Concentration of TAK-935 During Post-TAK-935 Dosing PET Scan Periods (Secondary), Number, nanogram per milliliter (ng/mL): TAK-935 50 mg 9.16; TAK-935 100 mg 11.3; TAK-935 200 mg 158; TAK-935 300 mg 56.2; TAK-935 600 mg 6.83
• Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) (Secondary), Number, percent change: TAK-935 50 mg -6.79; TAK-935 100 mg -14.82; TAK-935 200 mg -10.50; TAK-935 300 mg -12.41; TAK-935 600 mg -7.23

Adverse events

Time frame: Baseline up to Day 28

Other adverse events by term

• Results publication: Constantinescu CC, Brown T, Wang S, Yin W, Barret O, Jennings D, Tauscher J. Clinical Characterization of [18F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy. J Nucl Med. 2023 Dec 1;64(12):1972-1979. doi: 10.2967/jnumed.123.265912. PMID 37770111

• Medical Director, Study director, Takeda (Note: This product was divested to Mistrau Bio, Inc. in 2026)