P. Lockwood,1 J. Bell,1 L. Chen,1 J. Miceli,1 K. Macci,2 J. Van Winkle,2 B. Planeta,3 S. Henry,3 N. Nabulsi,3 R. Carson3; 1Pfizer Inc., Groton, CT, 2Pfizer Inc., New Haven, CT, 3Yale University, New Haven, CT

BACKGROUND: SAM760 is a 5HT6 receptor antagonist being developed for the symptomatic treatment of Alzheimer’s disease with neuropsychiatric symptoms. A prior PET study showed > 80% 5HT6 RO in the frontal cortex (FC) at clinical doses. In vitro binding shows SAM760 to be a 5HT2a antagonist and the purpose of this study was to measure 5HT2a RO in the FC and other brain regions of interest (ROI).
METHODS: This was an open‑label study planned for 3 cohorts of 4 subjects. RO was measured by PET imaging using the radioligand [11C]MDL100907. A 70 mg dose was evaluated in cohort one (C1) . Scans occurred predose, and from ~ 4 to 6 and 28 to 30 hr post dose. Venous and arterial samples were collected for assessing drug and tracer kinetics. Subsequent doses and scan times were dependent on C1 data and adaptive criteria. RO was derived from the % change in binding potential (BPND) relative to the predose value. BPND’s were estimated with a two-tissue model with arterial input function (2T) and 2-step simplified reference tissue model (SRTM2) with cerebellum as a reference.
RESULTS: Table 1 displays RO at the FC. The study was stopped based on the low C1 RO finding and stopping rules. SAM760 was well tolerated. Tracer images and SAM760 plasma levels were as expected.
CONCLUSION: Minimal to no binding of SAM760 to 5HT2a receptors was observed in cortical brain regions.

Estimated RO in FC based on 2T or SRTM2 method

Subject Age (yr) Gender Wt (kg) Time Post Dose (hr) Estimated Receptor Occupancy (%)
2T method SRTM2 method
1 49 M 104 3.5 -13.0 -6.5
24.8 -15.0 4.9
2 30 M 69 3.6 17.5 5.4
23.5 data not available; no arterial line 4.1
3 26 M 91 4.0 data not available; no arterial line -16.9
27.9 data not available; no arterial line -19.2
4 44 M 78 4.0 13.3 -11.1
27.5 16.0 -0.3