p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Abstract

The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…Preadministration of a high dose of 8-OH-DPAT blocks [ 11 C]WAY-100635 specific uptake in the frontal cortex substantially (Farde et al, 1997;Mathis et al, 1994). Administered during a PET scan, 8-OH-DPAT displaces [ 11 C]WAY-100635 (Mathis et al, 1994;Tsukada et al, 2001) and [ 18 F]MPPF (Shiue et al, 1997). In ex vivo studies in rats, 8-OH-DPAT blocks the binding of H]WAY-100635 (Hume et al, 1994), [ 11 C]WAY-100635 (Mathis et al, 1994) and [ 18 F]MPPF (Shiue et al, 1997).…”

“…Administered during a PET scan, 8-OH-DPAT displaces [ 11 C]WAY-100635 (Mathis et al, 1994;Tsukada et al, 2001) and [ 18 F]MPPF (Shiue et al, 1997). In ex vivo studies in rats, 8-OH-DPAT blocks the binding of H]WAY-100635 (Hume et al, 1994), [ 11 C]WAY-100635 (Mathis et al, 1994) and [ 18 F]MPPF (Shiue et al, 1997). Buspirone and ipsapirone at doses of 2 mg/kg blocked B50% of [O-methyl-3 H]WAY-100635 specific binding in all regions examined in an ex vivo study in rats, while 5 mg/kg buspirone occupied 61% of frontal cortex 5-HT 1A receptor in an [ 11 C]WAY-100635 PET study using a monkey (Farde et al, 1997).…”

Effect of Increased Serotonin Levels on [18F]MPPF Binding in Rat Brain: Fenfluramine vs the Combination of Citalopram and Ketanserin

“…The study was approved by the Animal Care Committee of the University of Groningen. Shiue et al (1997) for a comparable method). It was formulated into a 5% NaCl solution.…”

“…This time point is based on earlier studies which showed that 30 min after injection, MPPF binding reaches a state of transient equilibrium (Plenevaux et al, 2000b;Shiue et al, 1997). The brains were removed from the skull, frozen in isopentane (À801C), cut into 80 mm coronal slices in a cryostat at -101C, thaw mounted onto glass slides, exposed to a phosphor storage screen (Packard) for at least 10 halflife times (18-20 h) and scanned using the Cyclone storage phosphor system.…”

“…Peak levels were achieved 45 min after administration (Figure 1). uptake in the raphe nuclei, septum, and hippocampus and low uptake in the cerebellum (Ginovart et al, 2000;Passchier et al, 2000;Plenevaux et al, 2000a;Shiue et al, 1997). Region over cerebellum ratios ranged from approximately 1 in the striatum to around 10 in the dorsal raphe nucleus.…”