Evaluation of [¹⁸ F]2FP3 in pigs and non-human primates

So far, no suitable 5-HT₇ R radioligand exists for clinical positron emission tomography (PET) imaging. [¹⁸ F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs). Furthermore, we investigate species differences in 5-HT₇ R binding with [³ H]SB-269970 autoradiography in post-mortem pig, NHP, and human brain tissue. Specific binding of [¹⁸ F]2FP3 was investigated by intravenous administration of the 5-HT₇ R specific antagonist SB-269970. [³ H]SB-269970 autoradiography was performed as previously described. [¹⁸ F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB-269970 only resulted in decreased binding of 20% in the thalamus, a 5-HT₇ R-rich region. Autoradiography on post-mortem pig, NHP, and human tissues revealed that specific binding of [³ H]SB-269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [¹⁸ F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5-HT₇ R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5-HT₇ Rs in vivo and that part of the PET signal arises from targets other than the 5-HT₇ R.