piperidines and altanserin

Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.

Topics: Animals; Brain; Fluorine Radioisotopes; Fluorobenzenes; Ketanserin; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Swine; Tissue Distribution; Tritium

MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT(2A) antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4-benzoyl-piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [³H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound (8) with a moderate affinity toward the 5-HT(2A) receptor (K(i) = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (K(i) = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT(2A) receptor with the p-fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.

Topics: Binding, Competitive; Combinatorial Chemistry Techniques; Fluorobenzenes; Hydrophobic and Hydrophilic Interactions; Ketanserin; Ligands; Phenols; Piperidines; Protein Binding; Pyridines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists

Radiochemical labeling of MDL 105725 using the secondary labeling precursor 2-[(18)F]fluoroethyltosylate ([(18)F]FETos) was carried out in yields of approximately 90% synthesizing [(18)F]MHMZ in a specific activity of approximately 50MBq/nmol with a starting activity of approximately 3GBq. Overall radiochemical yield including [(18)F]FETos synthon synthesis, [(18)F]fluoroalkylation and preparing the injectable [(18)F]MHMZ solution was 42% within a synthesis time of approximately 100 min. The novel compound showed excellent specific binding to the 5-HT(2A) receptor (K(i)=9.0 nM) in vitro and promising in vivo characteristics.

Topics: Animals; Binding, Competitive; Brain; Fluorine Radioisotopes; Fluorobenzenes; Isotope Labeling; Ketanserin; Kinetics; Piperidines; Radioligand Assay; Radionuclide Imaging; Radiopharmaceuticals; Rats; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

To study the 5-HT(2A) receptors in the living human brain, using positron emission tomography (PET), two selective radiotracers are currently in use: [(18)F]altanserin and [(11)C]MDL 100907. It is, however, currently unknown to what extent data obtained with either tracer are directly comparable. The aim of this study was to compare binding characteristics of these two radiotracers in rat brain with respect to affinity (K(d)), receptor binding density (B(max)), binding potential (BP), and nonspecific binding. Further, binding kinetics, sensitivity towards competition with the endogenous transmitter serotonin, and the competitive/noncompetitive interaction between the two radioligands were evaluated. In addition, the selectivity of [(18)F]altanserin for the 5-HT(2A) receptor was assessed. The K(d) value of [(18)F]altanserin and [(3)H]MDL 100907 was in the order of 0.3 nM. B(max) in frontal cortex was 523 and 527 fmol/mg protein, respectively. The binding of [(18)F]altanserin was not influenced by blocking either the 5-HT(2B/2C) or the alpha(1)-adrenergic receptors. At 37 degrees C the association t(1/2) was 2.8 and 2.7 min and the dissociation t(1/2) was 11 and 13.5 min for [(18)F]altanserin and [(3)H]MDL 100907, respectively. Both radioligands were displaced by 5-HT, only at high concentrations; the K(i) value of 5-HT ranging between 650 and 3,300 nM. This indicates that binding of both radioligands in PET studies is not directly influenced by changes in endogenous 5-HT.Overall, the binding of [(18)F]altanserin and [(3)H]MDL 100907 to the 5-HT(2A) receptor was very comparable, showing selective high affinity binding in the subnanomolar range.

Topics: Animals; Binding, Competitive; Brain; Carbon Radioisotopes; Fluorine Radioisotopes; Fluorobenzenes; Ketanserin; Male; Piperidines; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists