Radiosynthesis and in vivo evaluation of a series of substituted super(11)C-phenethylamines as 5-HT sub(2A) agonist PET tracers

• Published in: European journal of nuclear medicine and molecular imaging 2011-04, Vol.38 (4), p.681-693
• Main Authors: Ettrup, Anders, Hansen, Martin, Santini, Martin A, Paine, James, Gillings, Nic, Palner, Mikael, Lehel, Szabolcs, Herth, Matthias M, Madsen, Jacob, Kristensen, Jesper, Begtrup, Mikael, Knudsen, Gitte M
• Format: Article
• Language: English
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-010-1686-8

Purpose: Positron emission tomography (PET) imaging of serotonin 2A (5-HT sub(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT sub(2A) receptors in their high-affinity state. We have previously validated [ super(11)C]Cimbi-5 and found that it is a 5-HT sub(2A) 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 [ super(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT sub(2A) receptor agonist PET tracers in the pig brain. Methods: Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90min in a high-resolution research tomography scanner. To evaluate 5-HT sub(2A) receptor binding, cortical nondisplaceable binding potentials (BP sub(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region. Results: After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT sub(2A) receptor distribution. The largest target-to-background binding ratio was found for [ super(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [ super(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT sub(2A) receptor selectivity in vivo. [ super(11)C]Cimbi-82 and [ super(11)C]Cimbi-21 showed lower cortical BP sub(ND), while [ super(11)C]Cimbi-27, [ super(11)C]Cimbi-29, [ super(11)C]Cimbi-31 and [ super(11)C]Cimbi-88 gave rise to cortical BP sub(ND) similar to that of [ super(11)C]Cimbi-5. Conclusion: [ super(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT sub(2A) receptor agonist binding in the living human brain with PET.