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PET Quantification of 5-HT_2A Receptors in the Human Brain: A Constant Infusion Paradigm with [¹⁸F]Altanserin

Departments of Psychiatry and Diagnostic Radiology, Yale University School of Medicine, New Haven
West Haven Veterans' Affairs Medical Center, West Haven, Connecticut

Correspondence: For correspondence or reprints contact: Christopher H. van Dyck, MD, Yale University School of Medicine, CB 2041, 333 Cedar St., New Haven, CT 06510.

ABSTRACT

[¹⁸F]altanserin has been used to label serotonin 5-HT_2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [¹⁸F]altanserin with PET. Kinetic modeling with [¹⁸F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. Methods: Eight healthy volunteers were injected with [¹⁸F]altanserin as a bolus (208 ± 9 MBq [5.62 ± 0.25 mCi]) plus constant infusion (65 ± 3 MBq/h [1.76 ± 0.08 mCi/h]) ranging from 555 to 626 min (615 ± 24 min) after injection. PET acquisitions (10–20 min) and venous blood sampling were performed every 30–60 min throughout the infusion period. Results: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [¹⁸F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V₃' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V₃' ranged from 1.57 ± 0.38 for anterior cingulate cortex to 1.02 ± 0.39 for frontal cortex. The binding potential V₃ (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f₁) was also calculated and ranged from 169 ± 41 for anterior cingulate cortex to 110 ± 42 for frontal cortex. From 6 h onward, the rate of change for V₃' and V3 was only 1.11 ± 1.69 %/h. Conclusion: These results demonstrate the feasibility of equilibrium imaging with [¹⁸F]altan-serin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiola-beled metabolites. The stability in V₃ and V₃' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT_2A receptor density.

Key Words: [¹⁸F]altanserin • 5-HT_2A receptor • serotonin • PET

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