TY - JOUR
T1 - Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET
AU - James, Michelle L
AU - Shen, Bin
AU - Nielsen, Carsten Haagen
AU - Behera, Deepak
AU - Buckmaster, Christine L
AU - Mesangeau, Christophe
AU - Zavaleta, Cristina
AU - Vuppala, Pradeep K
AU - Jamalapuram, Seshulatha
AU - Avery, Bonnie A
AU - Lyons, David M
AU - McCurdy, Christopher R
AU - Biswal, Sandip
AU - Gambhir, Sanjiv S
AU - Chin, Frederick T
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 18F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of 18F-FTC-146 for eventual clinical translation. Methods: The distribution and stability of 18F-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 18F-FTC- 146 stability in monkey plasma and human serum. Results: Biodistribution studies showed that 18F-FTC-146 accumulated in S1Rrich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated 18F-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 18F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of 18F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual 18F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of 18F-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 18F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that 18F-FTC- 146 has a longer half-life in human microsomes, compared with rodents. Conclusion: Together, these results indicate that 18F-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.
AB - 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 18F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of 18F-FTC-146 for eventual clinical translation. Methods: The distribution and stability of 18F-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 18F-FTC- 146 stability in monkey plasma and human serum. Results: Biodistribution studies showed that 18F-FTC-146 accumulated in S1Rrich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated 18F-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 18F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of 18F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual 18F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of 18F-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 18F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that 18F-FTC- 146 has a longer half-life in human microsomes, compared with rodents. Conclusion: Together, these results indicate that 18F-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.
KW - Animals
KW - Azepines
KW - Benzothiazoles
KW - Brain
KW - Chromatography, High Pressure Liquid
KW - Humans
KW - Ligands
KW - Magnetic Resonance Imaging
KW - Male
KW - Mice
KW - Microsomes, Liver
KW - Positron-Emission Tomography
KW - Protein Binding
KW - Radiopharmaceuticals
KW - Rats
KW - Rats, Sprague-Dawley
KW - Receptors, sigma
KW - Saimiri
KW - Tissue Distribution
KW - Tomography, X-Ray Computed
U2 - 10.2967/jnumed.113.120261
DO - 10.2967/jnumed.113.120261
M3 - Journal article
C2 - 24337599
SN - 0161-5505
VL - 55
SP - 147
EP - 153
JO - The Journal of Nuclear Medicine
JF - The Journal of Nuclear Medicine
IS - 1
ER -
