ORIGINAL ARTICLE 

Annals of Nuclear Medicine Vol. 14, No. 6, 461-466, 2000 

Search for PET probes for imaging the globus pallidus studied with rat brain ex vivo autoradiography 

Kiichi ISHIWATA,* Nobuo OGI,*,** Junichi SHIMADA,*** Wei-Fang WANG,* Kenji ISHII,* Akira TANAKA,** Fumio SUZUKI*** and Michio SENDA* 

*Positron Medical Center, Tokyo Metropolitan Institute of Gerontology 
**Showa Pharmaceutical University 
***Drug Discovery Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company 

We have evaluated the feasibility of using four positron emission tomography (PET) tracers for imaging the globus pallidus by ex vivo autoradiography in rats. The tracers investigated were [11C]KF18446, [11C]SCH 23390 and [11C]raclopride for mapping adenosine A2A, dopamine D1 and dopamine D2 receptors, respectively, and [18F]FDG. The highest uptake by the globus pallidus was found for [11C]SCH 23390, followed by [18F]FDG, [11C]KF18446 and [11C]raclopride. The receptor-specific uptake by the globus pallidus was observed in [11C]KF18446 and [11C]SCH 23390, but not in [11C]raclopride. Uptake ratios of globus pallidus to the striatum for [18F]FDG and [11C]KF18446 were approximately 0.6, which was twice as large as that for [11C]SCH 23390. In a rat model of degeneration of striatopallidal gamma-aminobutyric acid-ergic-enkephalin neurons induced by intrastriatal injection of quinolinic acid, the uptake of [11C]KF18446 by the striatum and globus pallidus was remarkably reduced. To prove the visualization of the globus pallidus by PET with [18F]FDG and [11C]KF18446, PET-MRI registration technique and advances in PET technologies providing high-resolution PET scanner will be required. The metabolic activity of the globus pallidus could then be measured by PET with [18F]FDG, and [11C]KF18446 may be a candidate tracer for imaging the pallidal terminals projecting from the striatum. 

Key words: [11C]KF18446, FDG, globus pallidus, adenosine A2A receptor, PET, ARG 


INTRODUCTION 

FROM THE FIRST DEMONSTRATION of human dopamine D2 receptors by positron emission tomography (PET) with [11C]N-methylspiperone,1 the dopaminergic neural transmission system in the basal ganglia has been studied well by mean of PET to diagnose dopamine-linked disorders such as Parkinson's disease, Huntington's disease and schizophrenia.2-5 The basal ganglia represents one of the most important subcortical structures in the motor circuit.6-8 Dopamine synthesizing ability and the density of dopamine uptake sites are measured to evaluate the pre-

 Received May 10, 2000, revision accepted September 28, 2000. 
 For reprint contact: Kiichi Ishiwata, Ph.D., Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1 Nakacho, Itabashi, Tokyo 173-0022, JAPAN. 
 E-mail: ishiwata@pet,tmig.or.jp 

synaptic functions in the striatum which represents a major input site in the motor circuit. On the other hand, the postsynaptic functions are evaluated by the dopamine D1 and D2 receptors. The former are localized on the striatonigral and striatoentopeduncular gamma-aminobutyric acid (GABA)-ergic-substance P neurons and striatal cell bodies projecting to the globus pallidus.9 The latter are present on the striatopallidal GABAergic-enkephalin neurons projecting to the globus pallidus.10-13 Several lines of evidence have suggested that the globus pallidus plays an important role in the control of voluntary movement and posture. Pathological changes in the globus pallidus have been demonstrated in many movement disorders such as progressive supranuclear palsy, corticobasal degeneration and pallidoluysian degeneration.14 Animal studies have shown that selective damage to the globus pallidus caused slowness of voluntary movements and involuntary posture.15,16 Recently treatment with a stereotactic surgery technique has been applied to many patients with Parkinson's disease, and the globus pallidus was empirically known to be onc of the most effective targets for selective ablation or stimulation.17,18 If the function of the globus pallidus is evaluated by PET, it will be of great value in investigating dopamine-linked disorders. So far no PET study focusing on the globus pallidus has been done, probably because of the small structure and low metabolic activity. 
 Recent advances in molecular and pharmacological studies on adenosine receptors have revealed that adenosine A2A receptors are highly enriched in the striatum, nucleus accumbens and olfactory tubercle,19-20 in which dopamine D1 and D2 receptors are localized at very high density. By the in situ hybridization technique, adenosine A2A receptor mRNA is found to be mainly expressed in striatopallidal GABAergic-enkephalin neurons as in the case of dopamine D2 receptor mRNA.22-25 In patients with Huntington's chorea with selective degeneration of the striatopallidal neurons, adenosine A2A receptor density is significantly reduced in the striatum, whereas the density is not significantly affected in patients with Parkinson's disease characterized by selective degeneration of nigrostriatal dopamine neurons.26 
 In developing PET ligands for mapping adenosine A2A receptors, we have found that [11C]KF18446, ([7-methyl-11C]-(E)- 8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine), is strongly taken up by the striatum, nucleus accumbens and olfactory tubercle as a selective ligand.27,28 We also noticed that this compound accumulated more in the globus pallidus than in the cerebral cortex and other brain regions. By in vitro autoradiography of the postmorten human brain. Svenningsson et al. showed that the adenosine A2A receptor ligand [3H]CGS 21680 was bound to the globus pallidus much more strongly than dopamine D1 and D2 receptor ligands.29 
 The aim of the present study is to find PET probes for imaging the globus pallidus. We evaluated the regional brain uptake of [11C]KF18446 in rats by ex vivo ARG and compared it with that of dopamine D1 and D2 receptor ligands, [11C]SCH 23390 and [11C]raclopride, respectively, and with that of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). Among the three kinds of receptors investigated, most of the adenosine A2A and dopamine D2 receptors and some of the dopamine D1 receptors are present on the GABAergic neurons projecting from the striatum to the globus pallidus as described above. It is reported that the glucose utilization ratio of globus pallidus to striatum measured by the [14C]2-dcoxy-D-glucose method was 0.53 and 0.50 in the conscious rat and monkey, respectively.30 


MATERIALS AND METHODS 

[11C]KF18446, [11C]raclopride, [11C]SCH 23390 and [18F]FDG were prepared in our laboratory. [14C]2-Deoxy-D-glucose was purchased from NENTM Life Science Products, Inc. (Boston, MA). Quinolinic acid was purchased from Sigma (St. Louis. MO. USA). Male Wistar rats were obtained from Tokyo Laboratory Animals Company (Tokyo, Japan). 
 The animal studies were approved by the Animal Care and Use Committee of Tokyo Metropolitan Institute of Gerontology. 
Regionlal brain uptake of radiolabeled tracers 
Each of the four tracers was intraveneously injected into rats (8-10 weeks old). The injected dose was 0.27-1.0 GBq/3.1-27 nmol/kg for [11C]KF18446, 0.26-0.58 GBq/4.2-33 nmol/kg for dopamine receptor ligands and 0.1 GBq/kg for [18F]FDG. Rats given [11C]KF18446 (n=8). [11C]raclopride (n=7), [11C]SCH 23390 (n=8) and [18F]FDG (n=4) were killed at 15, 30 and 45 min, respectively, after injection. The investigated times for [11C]KF18446 and [11C]raclopride were chosen as the uptake ratio of striatum to cerebellum, and/or the difference between the striatal uptake and cerebellar uptake, are optimal.27,31 Although these two parameters for [11C]SCH 23390 increased with time (unpublished data), ex vivo ARG of [11C]SCH 23390 was performed 30 min postinjection because of the short half-life of 11C (20.4 min). To evaluate the nonspecific uptake of the receptor ligands, a carrier-loading ligand (3 umol/kg) was also injected (n=4 for [11C]KF18446 and [11C]SCH 23390; and n=3 for [11C]raclopride). The brain was rapidly dissected, frozen and coronally cut into 20 um-thick sections with a cryotome (Bright Instrument Co., Ltd., Huntingdon. UK). The brain sections were dried on a hot plate at 60deg.C and were apposed to a storage phosphor screen (Phosphor Imager SI system, Molecular Dynamics, Sunnyvale CA, USA) until complete decay. The regional brain distribution was quantitatively evaluated as described previously.32 The regions of interest were placed on the striatum, globus pallidus, cerebral cortex and cerebellum, and the radioactivity level was expressed as the percentage of injected dose per gram tissue (%ID/g). The receptor-specific uptake in the striatum and globus pallidus was defined as the difference between uptake in the control and that in the blockade. 
 To compare the image of [11C]KF18446 directly with the image of glucose metabolism, [14C]2-deoxy-D-glucose (0.96 MBq) was intravenously injected into a rat weighing 345 g, and then 30 min later [11C]KF18446 (290 MBq/4.3 nmol) was also injected. 15 min later ex vivo ARG was performed. To visualize the distribution of 11C, the brain sections were exposed to a storage phosphor screen for two hours, and after decay-out of the 11C they were again brought into contact with a storage phosphor screen for three days to visualize the distribution of 14C. 

Regional brain uptake of [11C]KF18446 and [11C]SCH 23390 in the quinolinic acid-lesioned rat 
A rat model for degeneration of striatopallidal GABAergic neurons projecting to the globus pallidus was prepared by intrastriatal injection of quinolinic acid.33,34 Briefly, the rat was anesthetized with pentobarbital (50 mg/kg, i.p.) and the quinolinic acid solution (500 nmol in 2 ul) in 0.1 M phosphate buffer, pH 7.2, was infused into the right striatum (coordinates: anteroposterior=+ 0.0 mm, lateral=+ 3.0 mm, ventral=+ 4.0 mm from the bregma.35 At day 5 after the treatment, ex vivo ARG was performed at 30 min after injection of [11C]KF18446 (n=5) or [11C]SCH 23390 (n=5) as described above. 


RESULTS 

Figure 1 shows the ex vivo ARG images of four radiolabeled tracers [14C]2-Deoxy-D-glucose was used to compare directly with [11C]KF18446 in the same individual instead of [l8F]FDG. [14C]2-Deoxy-D-glucose and [18F]FDG gave almost the same images. [11C]KF18446 was strongly taken up by the striatum. The uptake by the globus pallidus was moderate, and the cortical uptake was weak (images of the cerebellum are not shown). The uptake of [14C]2-deoxy-D-glucose by the globus pallidus was lower than that by the striatum or cortex. [11C]SCH 23390 was taken up by the globus pallidus at a slightly higher level than in the cortex as [11C]KF18446 was, but the globus pallidus was not clearly visualized by [11C]raclopride. 
 The regional brain uptake of four tracers in the control and in the blockade is summarized in Table 1. The level of activity in the striatum was high in the order of [11C]SCH 23390, [18F]FDG, [11C]raclopride and [11C]KF18446, whereas that in the globus pallidus was high in the order of [11C]SCH 23390, [18F]FDG, [11C]KF18446 and [11C]raclopride. In the globus pallidus, the receptor-specific uptake of [11C]SCH 23390 and [11C]KF18446 was 76% and 63%, respectively, of total uptake, whereas that of [11C]raclopride was negligible. 
 To evaluate the imaging contrast, the ratio of uptake by the globus pallidus to that by the striatum was calculated (Table 1). The level of total activity of [11C]KF18446 and [18F]FDG in the globus pallidus was two thirds of that in the striatum, but the levels of the other two ligands in the globus pallidus were a third of that in the striatum. The specific uptake ratios of [11C]KF18446 and [11C]SCH 23390 were comparable to the total uptake ratios. 
 Figure 2 shows ex vivo autoradiograms of [11C]KF18446 and [11C]SCH 23390 in the rat brain after intrastriatal injection of quinolinic acid. On the lesioned side, the up-take of [11C]KF18446 by the striatum and globus pallidus was decreased to 54+-5% and 54+-0.13%, respectively, to that on the nonlesioned side, and the corresponding values for [11C]SCH 23390 were 30+-5% and 60+-0.24%. 


DISCUSSION 

The globus pallidus is a small structure for PET imaging in the human brain. But the volume is nearly comparable to that of the putamen, and is even greater than that of the caudate. PET scanners separately visualize the putamen and caudate with positron-emitting dopamine receptor ligands, dopamine transporter ligands or 6-[18F]fluoro-L-dopa. These tracers are taken up by the caudate and putamen to a similar level. So far no report has suggested accumulation of any tracers in the globus pallidus. 
 In the present study we measured the uptake of three receptor ligands and [18F]FDG by the globus pallidus in rats by ex vivo ARG to find a potential radioligand for imaging the globus pallidus by PET. The highest uptake by the globus pallidus was found for [11C]SCH 23390, followed by [18F]FDG, [11C]KF18446 and [11C]raclopride. The receptor-specific uptake by the globus pallidus was observed in [11C]SCH 23390 and [11C]KF18446, but not in [11C]raclopride. As for the uptake ratio of globus pallidus to striatum which is an index reflecting the imaging contrast, the total and receptor-specific uptake ratios of [11C]KF18446 were approximately 0.6, which is equivalent to the total uptake ratio of [18F]FDG and approximately twice as large as that for [11C]SCH 23390. These results are consistent with the finding by in vitro autoradiography in the postmorten human brain in which the adenosine A2A receptor ligand [3H]CGS 21680 was bound to the globus pallidus much more strongly than dopamine D1 and D2 receptor ligands.29 The uptake ratio of [18F]FDG is comparable with the glucose utilization ratio (0.53) measured by the [14C]2-deoxy-D-glucose method.30 
 In the previous study on a monkey, we demonstrated that PET with [11C]KF18446 clearly visualized adenosine A2A receptors in the caudate and putame.27 The PET camera used had a resolution of 4.0 mm full width at half maximum in the transaxial plane, but we did not notice the accumulatlon of [11C]KF18446 in the globus pallidus, when PET and MRI images were contrasted visually. Because the monkey brain is much smaller than the human brain, co-registration of PET images with MRI images should be essential to identify the globus pallidus.34,36,37 
 It is well known that adenosine A2A receptors are present on GABAnergic-enkephalin neurons projecting from the striatum to the globus pallidus, whereas dopamine D1 receptors are present on GABAnergic-substance P neurons projecting to the substantia nigra and globus pallidus.22-25 These neurons are degenerated by the striatal injection of excitotoxins such as quinolinic acid, kainic acid and ibotenic acid.38-42 In the present study the striatal injection of quinolinic acid remarkably reduced the striatal uptake of [11C]KF18446 and [11C]SCH 23390. The reduced uptake mainly reflects degeneration of the receptors, but not a change in blood flow, because we confirmed the remarkably reduced binding of each of the two ligands by in vitro binding assay with adjusting brain sections (unpublished data). The uptake of [11C]KF18446, but not of [11C]SCH 23390, was reduced in parallel in the globus pallidus and in the striatum in the present model. These results suggest that most neurons containing adenosine A2A receptors projecting from the striatum to the globus pallidus and that [11C]KF18446 is a marker of the terminals projecting from the striatum to the globus pallidus, and that some GABAnergic-enkephalin neurons containing dopamine D1 receptors in the striatum project to the globus pallidus. 
 In summary, among four tracers investigated, the highest uptake ratio of globus pallidus to the striatum observed for [18F]FDG and [11C]KF18446 was 0.6. To prove the visualization of the globus pallidus by PET with these tracers, the PET-MRI registration technique and advances in PET technology providing a high-resolution PET scanner will be required. The metabolic activity of the globus pallidus could then be measured with [18F]FDG, and [11C]KF18446 may be a candidate tracer for imaging the terminals projecting from the striatum to the globus pallidus. On the other hand, the receptor-specific uptake of [11C]SCH 23390, but not of [11C]raclopride, was observed in the globus pallidus, but the uptake ratio of the globus pallidus to the striatum was low, suggesting that the ligands for dopamine D1 and D2 receptors are not suitable for imaging the globus pallidus. 


ACKNOWLEDGMENTS 

This work was supported by a Grant-in-Aid for Scientific Research (B) No. 10558115 from the Ministry of Education, Science, Sports and Culture, Japan. The authors also thank Mr. S. Ishii for radiosynthesis. 


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