Evaluation of Serotoninergic System Alterations in Prodromal Parkinson's Disease with SNCA Mutations Using [11C]DASB and [11C]SB207145 PET Imaging
- Trial ID
- 2024-516610-38-00
- Protocol
- C24-41
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to investigate the early alteration of the **serotoninergic system** at the prodromal stage of Parkinson's disease (PD) using the radiotracers [11C]DASB and [11C]SB207145. This is conducted in participants with alpha-synuclein SNCA gene mutations (SNCA+ PD-), compared with healthy controls (SNCA- PD-). Understanding these early alterations is clinically relevant as it may provide insights into the pathophysiological mechanisms of PD and potentially aid in the development of early diagnostic markers or therapeutic targets.
Secondary objectives include:
- Investigating the evolution of the serotoninergic system in the continuum of PD progression from the prodromal stage to the symptomatic stage.
- Exploring the correlation between serotoninergic alterations and motor and non-motor symptoms in the continuum of PD course.
- Examining the correlation between serotoninergic and dopaminergic alterations in the continuum of PD course.
- Assessing the correlation between serotoninergic alterations, dopaminergic alterations, motor and non-motor symptoms, and wet biomarkers in the continuum of PD course.
- Investigating anatomical and functional changes on MRI between groups and measuring specific correlations with clinical scores.
Participants
The clinical trial involves a study population comprising both **males and females** aged between 18 and 80 years. Participants include individuals diagnosed with Parkinson's disease (PD) and those in the **prodromal phase of Parkinson's disease**, as well as healthy controls. The trial population was selected based on specific genetic criteria, including the presence or absence of alpha-synuclein SNCA gene mutations. Participants are required to be affiliated with or beneficiaries of the French social security system. The study includes both symptomatic PD patients and asymptomatic first-degree relatives of PD patients with known SNCA gene mutations. Participants must be able to perform planned assessments, including brain imaging, and provide informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as medication use are addressed, with participants required to hold certain medications before imaging procedures. The trial includes a vulnerable population, ensuring comprehensive representation across the study's demographic criteria.
Plans and Procedures
The clinical trial is designed to assess the impairment of the **serotoninergic system** during the prodromal phase of **Parkinson's disease** in individuals with SNCA gene mutations. This study employs a **randomized, double-blind, controlled** methodology to ensure the reliability and validity of the results. The trial will utilize the radiotracers [11C]DASB and [11C]SB207145 to investigate the early alterations in the serotoninergic system. The trial is expected to commence in September 2025 and conclude by March 2029, with the total duration of participant involvement being approximately four years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, genetic markers, and absence of other causes of Parkinsonism. Following the screening, participants will attend multiple follow-up visits where they will receive intravenous bolus injections or IV infusions of the investigational products, 11C-SB207145 and 11C-DASB, both formulated as solutions for injection. These visits will include assessments of the PET-binding potential of the radiotracers to serotonin transporter SERT and receptor 5-HT4, as well as comparisons between different participant groups. The end-of-study visit will involve final assessments and data collection to evaluate the primary and secondary endpoints, including correlations with clinical scores and imaging results.
The expected length of participant involvement is contingent upon their continued eligibility and adherence to study protocols. Conditions that may lead to early termination from the study include the development of exclusionary medical conditions, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable insights into the pathophysiology of Parkinson's disease and the potential role of serotoninergic system alterations in its prodromal phase.
Treatment
The clinical trial involves the administration of two experimental medications, **11C-SB207145** and **11C-DASB**, both of which are utilized to assess the impairment of the serotoninergic system during the prodromal phase of Parkinson's disease. **11C-SB207145** is a **solution for injection** containing the active substance **(1-(11C)methylpiperidin-4-yl)methyl 5-amino-6-chloro-1,4-benzodioxine-8-carboxylate**. This compound is administered via **intravenous bolus injection/IV infusion**. The maximum daily and total dose is 74 MBq/ml, with a treatment period limited to one day. The formulation is not pediatric and is chemically synthesized.
**11C-DASB** is also a **solution for injection**, with the active substance **3-amino-4-[2-[[methyl((111C)methyl)amino]methyl]phenyl]sulfanylbenzonitrile**. Similar to 11C-SB207145, it is administered through **intravenous bolus injection/IV infusion**. The maximum daily and total dose for 11C-DASB is 4 MBq/kg, and the treatment period is restricted to one day. This formulation is also not pediatric and is chemically synthesized. Both medications are provided by INSERM-ANRS and are used as test products in the trial. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the study protocol. Participant compliance with the dosing schedule is monitored to ensure adherence to the trial protocol.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the **PET-binding potential** of the radiotracer ligands [11C]DASB and [11C]SB207145. The primary endpoint involves determining the binding potential of these radiotracers to the serotonin transporter (SERT) and receptor 5-HT4, and comparing the results between participants with SNCA gene mutations (SNCA+ PD-) and those without (SNCA- PD-). Secondary endpoints include comparing the PET-binding potential across all participant groups and examining correlations between PET-binding potential and scores on motor and non-motor symptom assessment scales. Additionally, correlations will be assessed between PET-binding potential, DaTSCAN results, neuromelanin-sensitive MRI (NM-MRI) results, and measurements of blood and cerebrospinal biomarkers. Differences in anatomical and functional MRI images between groups and their correlations with clinical scores and PET data will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males and females with an age range of 18–80 years at the time of signing the informed consent
- Diagnosis of PD according to the 2015 Movement Disorder Society criteria, with bradykinesia AND at least ONE of the following: muscular rigidity, or resting tremor; with no other suspected cause of Parkinsonism for Symptomatic PD patients with and without SNCA mutation
- With documented point mutation or multiplication (i.e., duplication/triplication) mutation on the α-synuclein gene (SNCA) for Symptomatic PD patients with and without SNCA mutation
- Or without documented mutation in the SNCA gene for Symptomatic PD patients with and without SNCA mutation
- First degree relative of a PD patient with a known point mutation or multiplication in the SNCA gene (parent, sibling, or child) for Relatives of SNCA gene mutation carriers, without a diagnosis of PD
- Asymptomatic for PD symptoms, and not meeting Diagnosis of PD according to the 2015 Movement Disorder Society criteria for Healthy controls and Relatives of SNCA gene mutation carriers, without a diagnosis of PD
- Able to perform the assessments planned for the study (including brain imaging) according to investigator opinion
- Informed consent obtained from the patient or/ and a legal representative when appropriate
- For subjects taking any of the following drugs (Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or amphetamine derivative) must be willing and medically able to hold the medication for at least 5 half-lives before DaTSCAN imaging.
- Participant affiliated with or beneficiary of a French social security system or of such a regime
Exclusion Criteria
- Contraindication to MRI such as claustrophobia, epilepsy, severe movement disorders or inability to lay flat that, in the investigator's judgment, precludes the subject's safe participation in and completion of the study. Subjects with a history of working with metal (using grinders, etc.) should have a safety check for residual metal fragments in their eyes to avoid damage from the magnetic fields.
- Implanted devices such as stimulators, spinal rods, aneurysm clips, cardiac pacemaker, hearing device, metallic contraceptive device, insulin pump, artificial implants, peripheral or neuronal stimulator, intravenous catheter that would interfere with MRI interpretation
- Contraindication to PET imaging or DaTSCAN®
- Known Hypersensitivity to ioflupane or to any excipients of DaTSCAN®
- Significant brain abnormalities that could interfere with accurate brain imaging analysis
- Subjects treated with specific serotonin reuptake inhibitors, noradrenalin or serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase type A inhibitors, neuroleptics impacting the serotoninergic system or recreative drugs impacting the serotonergic system in the last 3 months
- Impaired comprehension interfering with an informed consent in the opinion of the investigator
- Pregnant and lactating women; Women of childbearing potential (WOCBP) tested positive in serum or urine pregnancy test (The following may be considered as highly effective contraception: progestogen-only or combined (estrogen and progestogen containing) hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (if the 22/58 SerIAL-PD_Protocol_V1.0_18032025 partner is the sole sexual partner of the WOCBP participant for the duration of the study) or abstinence (depending on the participant's lifestyle)).
- WOCBP without a highly effective contraception
- Participation in investigational drug trials within 30 days prior to screening or within 5 half-life of investigational product whatever the longest
- Active disease which could interfere with study conduct as per investigator’s judgement
- Any factor which might create an unjustified risk for the participant
- Minors or subjects benefiting from laws aimed at protecting vulnerable adults: subjects being deprived of liberty by judicial or administrative decision, subjects under guardianship /curatorship.
- For participants undergoing optional lumbar puncture (LP): Any contraindication to LP procedures, including but not limited to: a. Known or suspected structural abnormality of the lumbar spine, including but not limited to X-ray, MRI, or myelographic evidence of significant lumbar spine abnormalities, or other anatomical factors at or near the LP site that, in the opinion of the Investigator, may interfere with the performance of the LP, render repeated LPs difficult, or increase the risk of the procedure for the participant. b. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and might place a participant at an increased risk for intraoperative or postoperative bleeding. These could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities), known underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, von Willebrand’s disease, liver disease), clinically significant abnormal lab values increasing the risk of bleeding regarding platelets count, INR or PT or aPTT. - Low platelet count (below 50,000 cells/μL)(Hemostasis test must be done 72h max prior to the LP. A medical prescription will be sent to the participant to check whether his/her coagulation level is in accordance with this intervention.), - Screening values of International Normalized Ratio (INR), Prothrombin time (PT), or Activated Partial Thromboplastin Time (APTT) that are not within normal ranges (determined by the laboratory performing the analyses), - Taking any antiplatelet medication (e.g., aspirin >81 mg daily, clopidogrel, or nonsteroidal anti-inflammatory drugs [NSAIDs]) within 7 days prior to the planned LP or anticipated need for antiplatelet medication within 48 hours after an LP, - Taking anticoagulant medication (warfarin, heparinoids, and direct coagulation factor inhibitors, e.g., apixaban, dabigatran, rivaroxaban) c. Presence of intracranial hypertension d. Puncture site infections e. Patients treated with Deep Brain Stimulation.
- For participants undergoing optional skin sampling: any contraindication to this procedure including : - Anticoagulant or antiplatelet therapy, - History of hemostasis disorders, - Bleeding risk verified by a coagulation test
- Presence or known medical history of clinically significant neurological disorder other than PD
- Participant within the exclusion period in the National Register for participants of the French Ministry of Health.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Sept 2025 | 50 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
11C-SB207145 | Test | SOLUTION FOR INJECTION | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 74 | 1 | PRD11814931 |
11C-DASB | Test | SOLUTION FOR INJECTION | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 4 | 1 | PRD11814205 |