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

Abstract

So far, no suitable 5‐HT7R radioligand exists for clinical positron emission tomography (PET) imaging. [18F]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‐HT7R binding with [3H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [18F]2FP3 was investigated by intravenous administration of the 5‐HT7R specific antagonist SB‐269970. [3H]SB‐269970 autoradiography was performed as previously described. [18F]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‐HT7R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [3H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT7R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT7Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT7R.

Radiotracers for the Central Serotoninergic System

“…In addition, 95% of the collected signal was assigned to [ 18 F]2FP3 and not from a radiometabolite. In 2019, a complementary study on pigs and nonhuman primates was carried out [ 245 ]. Partial specificity of [ 18 F]2FP3 for the cerebellum (in monkeys) was revealed, clearly reflecting the difficulties in translating the results from one species to another.…”

Radiosynthesis and preclinical evaluation of [11C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT7 receptors

“…Figure 1 displays some key structures that have been used over the years. Especially derivatives of SB‐269970 appear promising and have attracted attention over the years . This is due to the high affinity and selectivity profile of SB‐269970 …”

“…Schematic overview of SB‐269970, examples of previously evaluated PET tracers for the 5‐HT 7 receptor and the potential PET tracer presented in this work: [ 11 C]Cimbi‐701…”

Benzoxazolone‐arylpiperazinyl scaffold‐based PET ligand for 5‐HT7: Synthesis and biological evaluation

“…(5-HT 7R ) positron emission tomography (PET) ligands, comprising SB269970, [ 11 C]DR4446, [ 18 F]2FP3, [ 18 F]ENL30, [ 18 F]ENL10, and many more (Hansen et al, 2019;Zhang et al, 2002) However, with limitations like nonspecificity, lower brain uptake, and biotransformation associated with these ligands, the development of new ameliorated receptor-specific high-affinity ligands is crucial (Matthys et al, 2011;L'Estrade et al, 2020;.…”