1. Establish the safety and tolerability of the 5-cyano-N-(4-(4-[11C]Methylpiperazin-1-yl)-2-(Piperidin-1-yl)Phenyl)Furan-2-carboxamide ([11C]CPPC) PET radioligand in ALS patients and controls
2. Examine whether [11C]CPPC PET uptake is elevated in brains of ALS patients and whether there is a correlation with clinical phenotype.
3. Correlate [11C]CPPC PET imaging with other ALS outcome measures and biofluid biomarkers
4. Examine longitudinal changes in [11C]CPPC PET imaging during disease course.

There are a paucity of reliable serum and cerebrospinal (CSF) biomarkers and validated neuroimaging techniques to aid in amyotrophic lateral sclerosis (ALS) diagnosis, prognosis, or pharmacodynamic insight. Positron emission tomography (PET) imaging is a technique that uses radioactive molecules attached to a ligand of interest which localizes to the desired target, allowing for visualization of the three dimensional distribution of the ligand's target receptor.

One of the upstream processes that are thought to lead to motor neuron degeneration in ALS is microglial dysfunction, resulting in the initiation of neuroinflammatory cascades. Macrophage colony stimulating factor 1 receptor (CSF1R) is found on microglia predominately in the brain, with low levels of expression in neurons and other neural cells, making it a promising target for studying microglial activation.

Given CSF1's potential role in ALS disease progression, and that its receptor (CSF1R) can be directly targeted, ligands binding this receptor are an area of interest for imaging in ALS. [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], is a positron-emitting, high-affinity ligand that is specific for CSF1R.

The aims of this study are as follows:

1. Establish the safety and tolerability of the [11C]CPPC PET radioligand in ALS patients and controls
2. Examine whether [11C]CPPC PET uptake is elevated in brains of ALS patients and whether there is a correlation with clinical phenotype.
3. Correlate [11C]CPPC PET imaging with other ALS outcome measures and biofluid biomarkers
4. Examine longitudinal changes in [11C]CPPC PET imaging during disease course.

Inclusion Criteria

1. Have the ability to understand the requirements of the study, provide written informed consent, understand and provide written authorization for the use and disclosure of Protected Health Information (PHI) [per Health Insurance Portability and Accountability Act (HIPAA) Privacy Ruling] and comply with the study procedures.

2. Men and women at least 18 years old.

3. Male patients, who have not had a vasectomy and a confirmed zero sperm count, must agree for the duration of the study to:

   • use a condom during sexual intercourse with female partners who are of reproductive potential AND to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) OR
   • male patient must agree to abstain from sexual intercourse during the study

4. Women must have a negative serum pregnancy test and practice an acceptable method of contraception or be of non-childbearing potential (post-menopausal for at least 2 years or who have undergone hysterectomy, oophorectomy or surgical sterilization). Women must not be breastfeeding.

5. Geographic accessibility to the study center and the ability to travel to the clinic for study visits.

6. Presence of a willing and able caregiver.

7. Diagnosis of ALS based on examination by the site PI, meeting El Escorial criteria for possible, laboratory-supported probable, probable or definite ALS or be a person without a diagnosis of ALS disorder.

8. Vital capacity ≥ 50% of predicted normal for age, height and gender measured in the seated position and the ability to lie supine for a period of 1 hour.

9. Agrees to the visit schedule as outlined in the informed consent.

10. Pre-study labs within normal range, or if abnormal, deemed not clinically significant by the site investigator.

Exclusion Criteria:

1. Weakness due to causes other than ALS.

2. Receipt of any investigational drug, device or biologic within 10 days of administration of study compound.

3. Use of anti-inflammatory medications, immunosuppressants, or benzodiazepines within 7 days of administration of study compound.

4. Any concomitant medical disease or condition limiting the safety to participate including, but not limited to:

   1. Coagulopathy
   2. Active infection

5. Any condition that the site PI feels may interfere with participation in the study.

6. Inability to provide informed consent as determined by the site PI.

7. Known clinical evidence of frontotemporal dementia.

8. Inadequate family or caregiver support as determined by the site PI.

9. Presence of any of the following conditions:

   1. Current drug abuse or alcoholism
   2. Unstable medical conditions
   3. Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening