Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers
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Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A receptor agonist PET tracers in the pig brain.
Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT2A receptor binding, cortical nondisplaceable binding potentials (BPND) were calculated using the simplified reference tissue model with the cerebellum as a reference region.
After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi-29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5.
[11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.
KeywordsPET tracer development 5-HT2A Agonist Porcine Serotonin receptors [11C]Cimbi-36
The technical assistance of Letty Klarskov, Mette Værum Olesen, Bente Dall and Jack Frausing Nielsen is gratefully acknowledged. This study was financially supported by the Lundbeck Foundation, University of Copenhagen, Faculty of Health Sciences, the Toyota Foundation, the John and Birthe Meyer Foundation, and by the EU 6th Framework program DiMI (LSHB-CT-2005-512146). [3H]MDL100907 was kindly provided by Prof. Christer Halldin, Karolinska Institute, Sweden. K i determinations at neuroreceptors were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract no. HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth, MD PhD, at the University of North Carolina at Chapel Hill, and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.
Conflicts of interest
- 5.Fitzgerald LW, Conklin DS, Krause CM, et al. High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action. J Neurochem. 1999;72:2127–34.PubMedCrossRefGoogle Scholar
- 9.Cumming P, Wong DF, Gillings N, Hilton J, Scheffel U, Gjedde A. Specific binding of [(11)C]raclopride and N-[(3)H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein. J Cereb Blood Flow Metab. 2002;22:596–604.PubMedCrossRefGoogle Scholar
- 13.Narendran R, Mason NS, Laymon CM, et al. A comparative evaluation of the dopamine D(2/3) agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum. J Pharmacol Exp Ther. 2010;333:533–9.PubMedCrossRefGoogle Scholar
- 14.Narendran R, Hwang DR, Slifstein M, et al. In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse. 2004;52:188–208.PubMedCrossRefGoogle Scholar
- 16.Shulgin A, Shulgin A. PIHKAL, a chemical love story. Berkeley, CA: Transform Press; 1991. p. 1–978.Google Scholar
- 31.Theobald DS, Putz M, Schneider E, Maurer HH. New designer drug 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric and capillary electrophoretic/mass spectrometric techniques. J Mass Spectrom. 2006;41:872–86.PubMedCrossRefGoogle Scholar