Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET

Abstract

The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.

Methods: The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.

Results: Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.

Conclusion: Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

Keywords: 18F; PET; σ-1 receptor.

Figures

FIGURE 1

Biodistribution of 18F-FTC-146 (11.0–18.5 MBq) in rats at 5, 15, 30, and 60 min after injection of radioligand (n = 4 for each time point). Error bars represent SEM.

FIGURE 2

Biodistribution of 18F-FTC-146 (11.0–18.5 MBq) at 60 min after injection of radioligand in baseline rats (no pretreatment) (n = 4) and rats pretreated with either haloperidol (1 mg/kg; n = 4) or BD1047 (1 mg/kg; n = 4). Error bars represent SEM.

FIGURE 3

Rat brain PET/CT and ex vivo autoradiography. (A) Baseline coronal PET/CT images 50–60 min after intravenous administration of 18F-FTC-146 (30–35 MBq). (B) PET/CT images from blocking study, involving pretreatment with S1R-specific ligand BD1047 (1 mg/kg) 10 min before radioligand (30–35 MBq) injection. (C) Autoradiography (top) and nissl/H&E staining (bottom) of coronal brain and muscle sections from baseline study. (D) Autoradiography (top) and nissl/H&E staining (bottom) of coronal brain and muscle sections from blocking study. BSt = brain stem; CC = corpus callosum; Cer = cerebellum; CP = caudate-putamen; Ctx = cortex; H&E = hematoxylin and eosin; H = hippocampus; HTh = hypothalamus; NO = nucleus oculomotor; RN = red nucleus; Th = Thalamus.

FIGURE 4

Percentage of intact radiotracer in rat plasma and brain at 15, 30, and 60 min after injection of 18F-FTC-146 (44.0–51.8 MBq). Error bars represent SEM.

FIGURE 5

Monkey brain PET/MR images from baseline dynamic imaging. Summed axial images are shown for 30–45, 60–75, and 105–120 min after administration of 18F-FTC-146 (92.5–111 MBq). Brain regions of interest are shown in MR images (top panel) and are labeled as (1) cingulate cortex, (2) frontal cortex, (3) striatum, (4) parietal cortex, (5) occipital cortex, (6) temporal cortex, (7) hippocampus, (8) cerebellum, and (9) vermis. ROIs = regions of interest.

FIGURE 6

Monkey brain PET/MR images 60–75 min after injection of radiotracer, and time–activity curves demonstrating uptake of radiotracer in different brain regions for baseline (18F-FTC-146) and blocking (18F-FTC-146 + haloperidol 0.1 mg/kg) studies. p.i. = after injection.