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NEUROPHARMACOLOGY

Effect of N-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide Monohydrate (FK960), an Antidementia Drug with a Novel Mechanism of Action, on Regional Cerebral Blood Flow and Glucose Metabolism in Aged Rhesus Macaques Studied with Positron Emission Tomography

Advanced Technology Platform Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan (A.N., S.N.); Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan (H.T., N.M.); Development Division, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan (S.K.); Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan (H.T.); Department of Biotracer Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan (A.N.); and The Medical and Pharmacological Research Center Foundation, Ishikawa, Japan (A.N., H.T., S.N.)

Received February 6, 2003; accepted April 2, 2003.

	Abstract

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Effect of N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960), a putative antidementia drug with a novel mechanism of action, on regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc) was examined in conscious aged rhesus macaques using positron emission tomography. Seven aged (21.6 ± 2.7 years) male rhesus macaques were subjected. FK960 was intramuscularly administered at doses of 0, 0.01, 0.1, or 1 mg/kg for seven consecutive days, in randomized order and in a blinded manner. Each subject was scanned four times in all, with at least 3-week intervals, after treatment with saline or three doses of FK960. Significant increases in rCBF in the left temporal and left frontal cortex, and in rCMRglc in the right hippocampus with adjacent cortex, were observed in the treatment group with 1 mg/kg FK960, without affecting any other cardiovascular and respiratory variables. No statistically significant change in any region was observed at doses of 0.01 or 0.1 mg/kg. These results suggested that FK960 restored the rCBF and rCMRglc deficits in brain areas responsible for cognitive functioning in aged rhesus macaques.

Aged rhesus macaques (Macaca mulatta) are considered to be a good model for human aging because of their characteristic behavioral and pathological features. Rhesus macaques were reported to develop age-associated impairments in performance on cognitive/memory tasks, and in their late teens, some animals show impairments in performance of certain spatial abilities, whereas senile plaques and amyloid deposits also formed (Price et al., 1992). PET studies in normal conscious aged macaques revealed decreased rCBF (Noda et al., 2002) and rCMRglc (Eberling et al., 1995; Noda et al., 2002) compared with young animals. Studies using cognitive/memory tasks in aged macaques also demonstrated the improvement effects of cognitive enhancers, physostigmine (Bartus and Uehara, 1979), or a nicotinic acetylcholine receptor agonist (Bontempi et al., 2001).

N-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960) is a putative antidementia drug with a novel mechanism of action. Several lines of evidence indicate that the memory-improving action of FK960 is mediated by activation of hippocampal somatostatinergic neurotransmission. In vitro studies have shown that FK960 enhances the magnitude of LTP in hippocampal slices through activation of somatostatinergic neurons (Matsuoka and Satoh, 1998); FK960 increased high K⁺-evoked somatostatin release from hippocampal slices without affecting basal release (Inoue et al., 2001); Repeated administration of FK960 dose dependently reversed the loss of axodendritic and axosomatic synapses observed in the hippocampal CA3 region of aged rats (Moriguchi et al., 2002). In behavioral studies, FK960 shared many of the properties of acetylcholinesterase inhibitors: FK960 reversed scopolamineinduced memory impairment in rodents (Yamazaki et al., 1996) and in nonhuman primates (Matsuoka and Aigner, 1997). Furthermore, FK960 improved memory impairment in aged rats and rats with lesions of the nucleus basalis magnocellularis (Yamazaki et al., 1996), a model in which acetylcholinesterase inhibitors have minimal efficacy. Recent report also demonstrated synergistic effects of FK960 combined with donepezil (Tokita et al., 2002), which would suggest FK960 have different mechanisms from cholinesterase inhibitors.

The present study was undertaken to examine the effect of FK960 on rCBF and rCMRglc in conscious aged macaques using PET. These parameters obtained in a well controlled experiment would provide objective indices of brain function in examining drug effect.

	Materials and Methods

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Animals. Studies were performed on seven aged (mean age, 21.6 ± 2.7 years; mean body weight, 7.24 ± 1.59 kg) male rhesus macaques. The animals were roughly equivalent to humans in their sixties. Animals were maintained and handled in accordance with the recommendations of the United States National Institute of Health and the research protocol was approved by the Central Research Laboratory, Hamamatsu Photonics K.K. (Hamakita, Japan). The animals had not been used in any previous pharmacological investigations. T1-weighted MRI images of the animals were obtained on an MRT-50A/II scanner (Toshiba, Tokyo, Japan) with a magnetic field strength of 0.5 T. Each animal had a specially designed head-holder (Onoe et al., 1994), used to fix the head to a monkey chair during PET scans. The animal was allowed to recover from the procedure for more than 1 month. The animals had been previously acclimated to chair restraint during repeated training sessions several times a week over more than 1 month before the initiation of the PET study.

Drug Testing. Solutions of FK960 (lot 670001; synthesized by Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan) were prepared on the 1st day of each test session by dissolving the compound in sterile physiological saline. The solutions were stored at room temperature for 7 days, where the stability had been tested (data not shown). An injection volume of 0.313 ml/kg was maintained irrespective of dose. FK960 was intramuscularly administered once a day at doses of 0.01, 0.1, or 1 mg/kg for seven consecutive days. The range of doses was around the doses at which FK960 showed a cholinergic restoration in conscious monkeys (Tsukada et al., 1999). Each subject was scanned four times, with at least 3-week intervals between each PET measurement, after treatment with saline or three doses of FK960, in randomized order and in a blinded manner. The washout duration was long enough FK960-induced increase in synaptic density to return to basal levels (Moriguchi et al., 2002). The last injection for each session was given just before a PET transmission scan (53 ± 11 min before rCBF study, 67 ± 12 min before rCMRglc study).

PET Experiment. PET scans were performed with a high-resolution animal PET scanner (SHR-7700; Hamamatsu Photonics K.K.), with transaxial resolution of 2.6-mm full-width at half-maximum in the center of the scan field, and a center-to-center distance of 3.6 mm (Watanabe et al., 1997). A ⁶⁸Ga-⁶⁸Ge-blank scan (120 min) was performed before each study. During catheterization of the left femoral artery to measure mean arterial blood pressure (MABP), heart rate, and arterial blood sampling, and catheterization of the saphenous vein for administration of tracers, subjects were transiently anesthetized with about 2% sevoflurane in a N₂O/O₂ gas mixture (N₂O/O₂, 7:3). After catheterization, anesthesia was immediately discontinued. Each animal's head was fixed to a monkey chair for PET scans with a head-holder and stereotaxically aligned parallel to the orbito-meatal (OM) plane with a laser marker, and a ⁶⁸Ga-⁶⁸Ge-transmission scan (30 min) was performed. From the start of each transmission scan, MABP and heart rate were continuously monitored with a life monitoring system (Nihon Kohden, Tokyo, Japan). More than 1 h after discontinuance of anesthesia, PaCO₂, PaO₂, and pH of arterial blood were measured (STAT PROFILE blood gas analyzer; Nova Biomedical Corp., Waltham, MA) to confirm the physiological condition of the subject. PET emission scans were performed with the subject's ears unplugged, eyes open, and in a dimmed light.

For rCBF measurement, [¹⁵O]H₂O (0.84 ± 0.22 GBq in saline of 2 ml) was injected intravenously. A 2-min emission scan consisted of 12 frames and was obtained after injection of [¹⁵O]H₂O. During that period, 24 timed arterial blood samples (0.2 ml) were withdrawn from a catheter placed in the femoral artery for measurement of arterial radioactivity using an ARC-2000 auto well gamma counter (Aloka, Tokyo, Japan).

Due to the very short half-life of ¹⁵O (2.037 min), the radioactivity rapidly decayed after the [¹⁵O]H₂O study and [¹⁸F]fluorodeoxyglucose (FDG) (0.56 ± 0.13 GBq in 2 ml of saline) was injected intravenously for the rCMRglc measurement. A 60-min emission scan consisted of 22 frames and was obtained after injection of FDG. During that period, 16 timed arterial blood samples (0.2 ml) were withdrawn for arterial radioactivity measurements. The blood samples obtained at 45 and 60 min after injection were also analyzed for blood glucose levels using COBAS READY (Nihon Roche, Tokyo, Japan).

Data Analysis. rCBF images were generated in accordance with an autoradiographic method (Herscovitch et al., 1983; Raichle et al., 1983). PET images from 0 to 90 s after injection and an arterial input function were used for calculation of rCBF images. A partition coefficient of 0.7, derived from preliminary kinetic analysis in young macaques (data not shown), was used.

rCMRglc images were generated in accordance with an autoradiographic method with an operational equation derived by Sokoloff et al. (1977) and modified by Phelps et al. (1979). The parameters derived by Reivich et al. (1985) were used for this calculation. PET images from 40 to 60 min after injection of FDG were used for the calculation of rCMRglc images.

Regions of interest (ROIs) were manually drawn on MRI images for each subject. Stereotaxic coordinates of PET and MRI were adjusted based on the OM plane with a head-holder attached to the head of each subject. ROIs were taken for the cerebellum, hippocampus with adjacent cortex, temporal cortex, occipital cortex, striatum, frontal cortex, and cingulate. rCBF and rCMRglc values were obtained in these ROIs. Each ROI of the hippocampus with adjacent cortex, temporal cortex, occipital cortex, striatum, and frontal cortex was divided into right and left. The ROI for the cingulate was divided into anterior and posterior.

Dose-response relationships for FK960's effects on rCBF, rCMRglc, and physiological parameters were determined. All data were represented as mean ± S.D. Statistical analysis was performed by two-way analysis of variance followed by paired Dunnett's multiple comparison, where the vehicle-treated group was set as the control group. A p value less than 0.05 was considered significant.

	Results

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Animals subjected to PET scanning procedures showed no overt behavioral signs of stress. Cardiovascular and respiratory variables measured immediately before the scans were within normal ranges in all groups and there were no significant changes in any parameters between groups at any dose levels of FK960 (Table 1). The present studies revealed a statistically significant increase in both rCBF and rCMRglc at the highest dose tested (1 mg/kg). As shown on Table 2, FK960 significantly improved rCBF in the left temporal and left frontal cortex, as well as rCMRglc in the right hippocampus with adjacent cortex. Figure 1 was a typical set of PET images that showed rCBF and rCMRglc images in control and 1 mg/kg FK960-treated condition.

View larger version (61K): [in this window] [in a new window]   Fig. 1. A typical set of PET images that showed CBF and CMRglc images in control and 1 mg/kg FK960-treated condition. Images are transverse slices of OM +3.6 (slice 7) to OM +28.8 mm (slice 14), with each slice 3.6 mm in thickness.

	Discussion

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The present study showed that FK960 significantly improved rCBF and rCMRglc in conscious aged macaques. Because the experiment was well controlled and no other cardiovascular or respiratory parameters were affected by FK960, the improvement reflected an essential improvement in brain activity. Previous investigations suggested a correlation between rCBF, rCMRglc, and cognitive function: rCBF and rCMRglc declined in both normal aged human and AD patients (Herholz et al., 1990; Minoshima et al., 1994; De Santi et al., 1995; Loessner et al., 1995); rCBF positively correlated with mini-mental state examination score (Jagust et al., 1997) and ADAScog (Nebu et al., 2001). Based on the evidence, several clinical PET studies for new antidementia drugs were also performed using rCBF and rCMRglc as surrogate endpoints of efficacy. Nordberg et al. (1998) reported that long-term treatment with tacrine restored rCBF and rCMRglc in AD patients. Harkins et al. (1997) reported that AD patients who showed increased rCBF with tacrine treatment were also associated with an improvement in mini-mental state examination score compared with AD patients with decreased rCBF. A clinical trial for propentofylline was performed using rCMRglc after stimulation with a verbal memory task representing functional reserve capacity (Mielke et al., 1998). In aged macaques, a relationship between age-dependent memory impairment and rCMRglc decline was suggested (Eberling et al., 1997). Therefore, it is conceivable to assume that the improvement in rCBF and rCMRglc caused by FK960 may reflect an improvement in cognitive function.

In the present results, rCBF in the left temporal and left frontal cortex and rCMRglc in the right hippocampus with adjacent cortex were significantly increased at dose of 1 mg/kg (Table 2), although there might have been a trend of increase in all cortical regions in rCBF and rCMRglc. The increase in rCBF and rCMRglc was about 10 to 20%; however, the difference between aged and young animals in rCBF and rCMRglc was only about 20 to 30% (Noda et al., 2002); therefore, the increase may not be substantially so small. In previous clinical PET studies, deficits in the temporal and frontal cortices were commonly observed in both normal aging (De Santi et al., 1995) and AD patients, and rCMRglc improvement in these regions was also observed in AD patients treated with tacrine (Nordberg et al., 1998). Even in rhesus macaques, the left temporal cortex was most affected in aged animals (Eberling et al., 1995). The effect of FK960 might tend show up in these well affected regions. Another possibility is the precedence of rCBF improvement compared with rCMRglc improvement resulted from the different mechanisms underlying in these effects. In AD patients, rCBF improvement due to long-term treatment with tacrine occurred after several weeks, whereas rCMRglc improvement occurred only several months after the initiation of treatment (Nordberg et al., 1998). Therefore, longer treatment might be needed for rCMRglc improvement. In the present results, there seemed to be a differential effect between two parameters and a difference in laterality. Figure 1 was a typical set of PET images that may show essentially no differential effect and no difference in laterality. Not only a limited spatial resolution of PET scanner, response to a drug was also suggested to be variable across subjects in aged animals (Bartus and Uehara, 1979; Eberling et al., 1995); therefore, the results might be possibly disturbed in some degree.

Although the mechanisms by which FK960 increases rCBF and rCMRglc still remain to be fully elucidated, previously obtained evidence supports the following: FK960 directly facilitates development of LTP in the hippocampus and also selectively enhances release of somatostatin from the hippocampus (Matsuoka and Satoh, 1998; Inoue et al., 2001). Indirect activation of the cholinergic-system by FK960 was also implicated in scopolamine-induced amnesia in rhesus macaques (Tsukada et al., 1999). Because cholinergic activation was known to increase rCBF as well as somatostatin had a vasodilative effect in artery (Dezsi et al., 1996), rCBF improvement by FK960 was suggested to be mediated by both these system. rCMRglc improvement in the hippocampus was also supported by the evidence that FK960 facilitated LTP in hippocampus (Matsuoka and Satoh, 1998). Repeated treatment with FK960 for either 3 or 21 days dose dependently increased the density of axodendritic and axosomatic synapses in the hippocampal CA3 region of aged rats (Moriguchi et al., 2002), which may cause rCMRglc improvement in the hippocampus through the activation of neuronal cells.

In conclusion, the present PET studies showed the effect of FK960 improving rCBF and rCMRglc in conscious aged macaques. This supports previous data showing the effects of FK960 in various amnesia models. The present study also demonstrates the potential utility of animal PET in pharmacological studies.

	Acknowledgements

 
We are grateful to Dr. Satoshi Nakanishi (Suzuka University of Medical Science and Technology) for MR image acquisition, Shingo Nishiyama and Masami Futatsubashi for the synthesis of [¹⁵O]H₂O and [¹⁸F]FDG, Dr. Hiroyuki Ohba for PET data analysis, and Take-haru Kakiuchi for providing technical assistance in animal experiments. We thank Dr. John Sharkey (Fujisawa Institute of Neuroscience in Edinburg, Edinburgh, UK) and Dr. Keizo Yoshida for valuable comments in preparing the manuscript.

	Footnotes

 
DOI: 10.1124/jpet.103.050245.

ABBREVIATIONS: rCBF, regional cerebral blood flow; rCMRglc, regional cerebral metabolic rate of glucose; PET, positron emission tomography; AD, Alzheimer's disease; LTP, long-term potentiation; MRI, magnetic resonance imaging; MABP, mean arterial blood pressure; OM, orbito-meatal; FDG, fluorodeoxyglucose; ROI, region of interest.

Address correspondence to: Akihiro Noda, The Medical and Pharmacological Research Center Foundation, Wo-32, Inoyama-machi, Hakui, Ishikawa 925-0613, Japan. E-mail: anoda{at}mprcf.or.jp

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