Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7 receptor PET neuroimaging

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

“…However, further chemical modifications within the structure of SB-269970A have resulted in the identification of a structurally related analogue SB-656104A (3, Figure 1), having an improved pharmacokinetic profile with ~four-fold longer half-life in vivo compared to SB-269970-A. [9] Another example of the development of a well-known 5-HT 7 R antagonist DR-4004 (5, Figure 1) showed that the chemical modification of sites expected to be susceptible to oxidative metabolism, resulted in the new series of compounds with better metabolic stability and bioavailability. Among them, compound [ 18 F]2F3P3 (4, Figure 1) showed the most promising results during studies in vitro, but its poor brain penetration, partially reversed after pharmacological inhibition of P-glycoprotein, was determined in assays in vivo.…”

“…[9] Another example of the development of a well-known 5-HT 7 R antagonist DR-4004 (5, Figure 1) showed that the chemical modification of sites expected to be susceptible to oxidative metabolism, resulted in the new series of compounds with better metabolic stability and bioavailability. As the result, the promising biphenyl derivatives were obtained which displayed higher (9) or similar (10) metabolic stability to reference 5-HT 7 receptor ligand LP-211 (65% and 36% of parent compound recovery after incubation with rat hepatic S9 fraction), and lower or comparable with marketed arylpiperazine drugs, such as tandospirone and etoperidone. [10] Similar modifications among the aminotriazine-derived 5-HT 7 R antagonists (6, Figure 1), by introduction of fluorine to block metabolic hydroxylation, also improved the metabolic stability and raised bioavailability from 12% to 57%.…”

PET Tracers for Serotonin Receptors and Their Applications

“…11) and [ 18 F]4FP3 (K i = 14 nM, Figure 11) show specific binding in vitro in brain sections of rats [175]. In vivo studies in cats show excellent brain uptake, regional distribution and specific binding for [ 18 F]2FP3 [176]. [ 11 C]CIMBI-806, a dimethoxy biphenyl analogue (K i = 8.6 nM, Fig.…”

Paracrine control of steroidogenesis by serotonin in adrenocortical neoplasms

“…In fact, positron emission tomography (PET)-scan imaging may soon allow investigating the distributions and densities of serotonergic receptors actually expressed in the adrenals for the clinical management of primary adrenal diseases. Indeed, numerous radiolabeled specific ligands of G-protein coupled receptor (GPCR) membrane receptors for PET-scan, including those targeting the 5-HT4 and 5-HT7 receptors, have been developed during the last years (Colomb et al, 2014;Zimmer and Le Bars, 2013). Especially, radiolabeled 5-HT4 receptor ligands are already used for functional brain imaging in man (Marner et al, 2010).…”