PET scan study examining the sigma1 receptor with a first-in-human radioisotope

The purpose of this study is to perform a thorough evaluation of (S)-[ 18F] FBFP and (R)-[ 18F] FBFP, sigma-1 radiotracers labeled with fluorine-18 [18F] in healthy participants to characterize its pharmacokinetic, metabolic and in vivo binding profile. Several lines of evidence have indicated the significance of sigma-1 receptor in the pathophysiology of Alzheimers disease (AD) and other neuropsychiatric disorders. In addition, sigma-1 receptors have been implicated in other neurologic diseases including Parkinsons disease (PD), amyotrophic lateral sclerosis (ALS), and Huntingtons disease (HD), as well as psychiatric disorders such as depression and schizophrenia. Therefore, it is an important target for the investigation of neuropsychiatric disorders and drug development. The ability to image and quantify sigma-1 receptor in vivo with radioligand for Positron Emission Tomography (PET) will enable us to elucidate its role in the diagnosis and treatment of AD and other neuropsychiatric disorders, and to investigate target engagement of sigma-1-targeted drug candidates. This study is expected to last up to four years, including recruitment and data analysis. Study Population: Adult male and female subjects, aged 18-60, who are in general good health, meet the inclusion criteria, and who do not meet any of the exclusion criteria will be sought to complete the study. Up to 120 healthy subjects may be screened in order to enroll 60 subjects into the three parts below.

In Part 1, we will conduct an evaluation study to assess the metabolic and pharmacokinetic properties of the novel sigma-1 imaging tracers (S)-[18F]FBFP and (R)-[18F]FBFP in humans. Five healthy subjects will undergo one single injection of (S)-[18F]FBFP and PET scan. Another five healthy subjects will undergo one single injection of (R)-[18F]FBFP and PET scan each. A total of 10 healthy subjects will be included in Part 1. Each subject will also undergo one MR scan for anatomical identification of brain regions. In Part 2, we will conduct a test/retest study of the novel sigma-1 imaging tracers (S)-[18F]FBFP and or (R)-[18F]FBFP in humans, to characterize pharmacokinetic behavior and determine the reliability and reproducibility of in vivo pharmacokinetic parameter measurements. A total of up to 20 10 healthy subjects will undergo two PET scans on two separate days with either (S)-[18F]FBFP or (R)-[18F]FBFP. 10 subjects will scan with (S)-[18F]FBFP and 10 subjects will scan with (R)-[18F]FBFP. Each subject will also undergo one MRI scan for anatomical identification of brain regions. In Part 3, we will conduct a test-blocking study to assess specific binding levels of (S)-[18F] FBFP and or (R)-[18F]FBFP in humans.

A total of 20 10 healthy subjects will undergo two PET scans on two separate days, with the second scan at 4 h (Tmax) after an oral dose of 10 mg donepezil. 10 subjects will scan with (S)-[18F]FBFP and 10 subjects will scan with (R)-[18F]FBFP. Each subject will also undergo one MRI scan for anatomical identification of brain regions. Subjects that complete a single scan in Part 1 may return to complete a retest scan in Part 2 OR a blocking scan in Part 3. This will include up to 5 subjects, as only one tracer will proceed to Part 2 and 3. Protocol and Consent Revision History: Version #1 and #2 were submitted to and reviewed by the FDA. Additional edits have been added in response to FDA recommendations included in the study may proceed letter. Protocol version 3, with tracked changes, is being submitted for initial IRB review. Please refer to the revision history on p.2 of the protocol for details. Version #1 and #2 of the protocol and consent have been uploaded for inclusion in the IRB record.

Adult male and female subjects (up to 30 total), aged 18-60, who are in general good health, meet the inclusion criteria, and who do not meet any of the exclusion criteria will be eligible for enrollment into the study in parts 1, 2, or 3.