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.

MicroPET imaging of 5-HT1A receptors in rat brain: a test–retest [18F]MPPF study

“…The hippocampus displayed the highest radioactivity, followed by septum, medial prefrontal cortex and raphe nuclei. A similar distribution pattern has also been reported using in vitro [19,33,43,44] or ex vivo [45,46] The present report provides regional estimates of [ 18 F] MPPF BP, k 2 and R 1 values for rat brain. As shown in Table 3, the BP values were in the same range as those previously reported in various species using PET.…”

Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: A continuous infusion PET study in conscious monkeys

“…After administration of [ 18 F]MPPF, the regional uptake of radioactivity was in agreement with previous results in nonhuman primates and with known 5-HT 1A receptor localization, with the highest uptake in the frontal cortex, cingulate cortex, and hippocampus, and low uptake in the cerebellum (Kung et al, 1996;Mengod et al, 1996;Plenevaux et al, 2000a;Shiue et al, 1997) (Fig. 2).…”

“…2). After bolus administration of [ 18 F]MPPF, the distribution and clearance were slower than those reported for the anesthetized cynomologus monkey (Shiue et al, 1997), and more rapid than for [ 11 C]WAY-100635 and analogues Osman et al, 1998;Pike et al, 1998;Tsukada et al 2001) (Fig. 3).…”

5‐HT1A receptor imaging in the human brain: Effect of tryptophan depletion and infusion on [18F]MPPF binding

“…After administration of [ 18 F]MPPF, the distribution of radioactivity was in agreement with previous results and with known 5-HT 1A receptor localization, with the highest uptake in the MTC and low uptake in the cerebellum (Ginovart et al, 2000;Le Bars et al, 1998;Passchier et al, 2000Passchier et al, , 2001Plenevaux et al, 2000;Shiue et al, 1997).…”