Fluselenamyl: Toxicology Studies in Mice, and Automated Synthesis of 18F-Fluselenamyl

Objectives: ¹¹C-PiB continues to be widely investigated diagnostic amyloid imaging tracer for the detection of Alzheimer’s disease (AD), while ¹⁸F- Florbetapir, ¹⁸F-Flutemetamol, and ¹⁸F-Florbetaben are FDA approved. However, these tracers are not robust in detecting diffuse Aβ plaques, a critical target at the prodromal stages of the disease, included in the revised NIAAA (National Institute on Aging and Alzheimer’s Association) criteria for detecting AD. This drawback in detecting the earlier form of the disease by these tracers, could lead to inefficient patient stratification thus mitigating the benefits obtained from the therapeutic drugs. To further complement noninvasive imaging resources for detecting AD at prodromal stages and enable molecular-specific imaging without confounded off-target effects, we have recently reported preclinical development and validation of ¹⁸F-Fluselenamyl that demonstrates characteristics of translatable Aβ specific imaging agents while also binding the diffuse plaques in neuropathologically confirmed AD tissues. Herein, we report the toxicology studies and automated synthesis of ¹⁸F-Fluselenamyl under GMP conditions.

Methods: Toxicology studies were performed via administering of single dose 2-week study. Automated synthesis was performed on GE module in FDA approved GMP facility.

Results: Fluselenamyl showed no signs of adverse effect on blood chemistry in two week single injection toxicology studies. Following intravenous administration of Fluselenamyl (500µg/kg; 243-fold) in mice (40 mice: 20 male and 20 female; 6-7 weeks of age; 20-25g ±10%), all mice were monitored continuously for clinical observations (physical, behavioral, and loss of body weight (> 20% in 1 week). Compared with vehicle treated counterparts (1 day post- and 14^th day-post injection), the unlabeled Fluselenamyl demonstrated no statistically significant effects on blood chemistry biomarkers (blood urea nitrogen (BUN), Creatinine, Glucose, total protein, albumin, bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), serum alkaline phosphatase (SAP), Ca, P, Na, K levels) and no noticeable pathological findings in sections of tissues, such as brain, heart, lungs, liver, kidney, spleen, pancreas, intestinal tract, stomach, testicles, male accessory sex glands, uterus/cervix/vagina, ovaries, adrenals, mesenteric lymph nodes, and thymus. Finally, ¹⁸F- Fluselenamyl was synthesized using automated modules under GMP compliance with high radiochemical yield and purity.

Conclusions: Fluselenamyl does now show any significant pharmacological effects in mice and the radiotracer is readily translated into automation phase under GMP conditions. Further assessment of 18F-Fluselenamyl dosimetry and safety profiles in humans are underway.