Search

A series of 4'-substituted phenyl-4-piperidinylmethanol and benzoyl-4-piperidine derivatives was synthesized as potential novel serotonin 5-HT2A receptor ligands that can be radiolabeled for in vivo brain imaging. Compounds were prepared by alkylation of 4-substituted benzoyl-4-piperidine with an iodo- or fluoro-substituted phenylalkyl halide followed by reduction with sodium borohydride. Potency of novel compounds was determined by in vitro radioreceptor affinity assays selective for serotonin 5-HT2A receptors. Potent compounds were further evaluated for selectivity at serotonin-2A versus 2C, 6, and 7, as well as dopamine D2 and adrenergic alpha1 and alpha2 receptors. The novel compound (4-fluorophenyl)-(1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl])methanol was particularly promising with high 5-HT2A potency (K(i) = 1.63 nM) and300-fold selectivity over other 5-HT receptor types.

The test/retest reproducibility of brain measures of 5-HT2A receptors with positron emission tomography (PET) and [ 18 F]deuteroaltanserin was examined in a group of eight healthy human subjects. PET measures of 5-HT2A receptors were obtained under an equilibrium paradigm, with a 40-min PET acquisition starting approximately at 300 min (308±11 min) after bolus plus constant infusion of the radiotracer. Three brain outcome measures were obtained at equilibrium, V 3 (ratio of specific brain uptake to free parent plasma concentration of radiotracer), V 3 ′ (ratio of specific brain uptake to total parent plasma concentration) and RT (ratio of specific to non-displaceable brain uptakes). V 3 ′ and RT had high test/retest reproducibility, as measured by mean intra-subject% change for cortical brain areas of 14.1 and 11.0%, respectively. They also had high reliability, as measured by mean intra-class correlation coefficients (ICC) for cortical brain areas of 0.86 and 0.88, respectively. V 3 had low test/retest reproducibility, due to high variability in the measures of free parent tracer in plasma. This study supports the feasibility of equilibrium imaging of 5-HT2A receptors with PET and [ 18 F]deuteroaltanserin. The equilibrium imaging method with [ 18 F]deuteroaltanserin allows a single acquisition and blood measurement to provide an image whose pixel values equal a receptor volume of distribution. Since the single image pixel values are proportional to receptor densities, the images can be used in pixel-by-pixel statistical methods, such as SPM, to assess the distribution and density of 5-HT2A receptors in neuropsychiatric disorders.

F-18 and H-2 dual-labeled altanserin (3, [18F]d-ALT), a novel PET tracer for 5-HT2A receptors with metabolically resistant properties, was synthesized by [18F]fluoride displacement of the corresponding deuterated nitro precursor in 32% yield (EOB) in 108 min with radiochemical purity 95% and specific activity >1000 mCi/μmol (EOS). The key intermediate ethyl N-(2-chloroethyl-2,2-d2)carbamate (7) was obtained by LiA1D4 reduction of a glycine ester (93%), chlorination and carbamoylation (79%). 4-(4-Nitro-benzoyl)piperidine (13) was synthesized (60%) by improving the published coupling reaction of p-nitrophenyltrimethylstannane (10), obtained from p-iodonitrobenzene and (CH3)6Sn2 (94%), with 1-benzoylisonipecotic acid chloride (11) followed by acid hydrolysis. 13 was alkylated with 7 (82%), hydrolyzed and condensed with methyl o-isothiocyanatobenzoyate to provide with the precursor deuteronitroaltanserin (4, 75%). Copyright © 1999 John Wiley & Sons, Ltd.

A one-pot and efficient conversion of aryl- and acyl-substituted methyl alcohols into the corresponding chlorides is described, which involved tosylation with tosyl chloride and triethylamine in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in CH2Cl2, followed by methanol-facilitated replacement of the tosylates with chloride. This mild method is readily amenable to large-scale synthesis.

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT(2A) receptor radiotracer [(18)F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [(18)F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical R(T) (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34-78%) for [(18)F]deuteroaltanserin than for [(18)F]altanserin. In contrast, the binding potential (Bmax/K(D)) was similar between radiotracers. [(18)F]Deuteroaltanserin cortical activity was displaced by the 5-HT(2A) receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [(18)F]deuteroaltanserin is essentially equivalent to [(18)F]altanserin for 5-HT(2A) receptor imaging in the baboon.

ABSTRACT. [ 18 F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT 2A ) receptors. The deuterium substitution of both of the 2′-hydrogens of altanserin ([ 18 F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [ 18 F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an 18 F-labeled tracer (T 1/2 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [ 18 F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [ 18 F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [ 18 F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V ′ 3 (ratio of specific uptake to total plasma parent concentration) and the binding potential V 3 (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [ 18 F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [ 18 F]deuteroaltanserin and suggest that it may be superior to [ 18 F]altanserin as a PET radioligand.

Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11 C]iomazenil and [ 123 I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11 C or 123 I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max / K d ) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.

A complete remote control system was constructed for production of the PET 5-HT2A ligand [18F]altanserin by nitro-for-fluoro exchange. Comparing with published methods, the key features include (1) conducting azeotropic distillation and nucleophilic displacement in an open vessel heated by a commercial microwave oven; (2) purifying the product by a single HPLC procedure and (3) removing HPLC solvent by solid phase extraction. The preparation took 114 min with 23% yield and high quality.