ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 9, No. 3, 131-136, 1995 

Initial clinical experiences with dopamine D2 receptor imaging by means of 2'-iodospiperone and single-photon emission computed tomography 
Yoshiharu YONEKURA,*,** Hideo SAJI,*** Yasushi IWASAKI,** Tatsuro TSUCHIDA,*,** Hidenao FUKUYAMA,** 
Akira SHIMATSU,** Yasuhiro IIDA,** Yasuhiro MAGATA,** Junji KONISHI,** Akira YOKOYAMA*** 
and Hiroshi SHIBASAKI** 

*Biomedical Imaging Research Center, Fukui Medical School
 **Faculty of Medicine and ***Faculty of Pharmaceutical Sciences, Kyoto University 

Dopamine D2 receptor imaging was performed with 123I labeled 2'-iodospiperone (2'-ISP) and single-photon emission computed tomography (SPECT) in 9 patients : 4 with idiopathic Parkinson's disease, 2 with parkinsonism, 1 with Wilson's disease and 2 with pituitary tumor, and the results were compared with the data for 9 normal subjects. Following an intravenous injection of 123I-2'-ISP, early (within 30 min) and late (between 2 and 4 hr) SPECT images were obtained by means of a multi-detector SPECT scanner or a rotating gamma camera. In normal subjects, early SPECT images demonstrated uniform distribution of radioactivity in the cerebral gray matter and cerebellum reflecting regional cerebral blood flow, whereas late SPECT images showed high radioactivity only in the basal ganglia. All the patients with Parkinson's disease also demonstrated symmetrical basal ganglia uptake in the late SPECT images, but it was diminished in parkinsonism and Wilson ' s disease. One patient with a growth hormone-producing pituitary tumor had a positive uptake in the tumor. These preliminary clinical data demonstrated that 2'-ISP can be used for SPECT imaging of D2 dopamine receptors and may be of clinical value for the diagnosis and planning of the treatment of neurological diseases. 

Key words: SPECT, dopamine D2 receptor, 123I-2'-rodosprperone (2'-ISP) movement disorder pituitary tumor 

INTRODUCTION 

OVER THE PAST DECADE there has been considerable interest in the development of radiopharmaceuticals for receptor imaging with single-photon emission computed tomography (SPECT).1 Although positron emission tomography (PET) still plays an important role in neuroscience research for understanding the biochemical mechanism of the neurotransmission function of the living human brain, SPECT is now expected to become a valuable tool in clinical nuclear medicine. 

Iodine-123 labeled 2'-iodospiperone (2'-ISP) is one of the butyrophenone derivatives developed for SPECT imaging of dopamine D2 receptors.2 Previous in vitro and in vivo animal experiments demonstrated specific binding of 2'-ISP to D2 receptors with high affinity.2,3 Consequently the validity of in vivo SPECT imaging in human brain was confirmed in normal subjects.4 Compared with N-methylspiperone, which is another butyrophenone derivative used for PET imaging,5 2'-ISP showed slightly less affinity with D2 receptors and negligible binding to serotonin receptors. In addition, the relatively long halflife of iodine-123 (T1/2 = 13 hr) compared with the 20 min half life of carbon-11 makes it possible to measure the radioactivity over several hours. These characteristics allowed the evaluation of the specific receptor binding in basal ganglia with a simple equilibrium approach with the cerebral cortex as a reference region.4,6 In this article we report the first clinical experiences may therefore also be of clinical value for predicting the therapeutic effect of a dopamine agonist such as bromocriptine on pituitary adenoma. Obviously more extensive studies will be needed to confirm the clinical role of receptor imaging with SPECT. 

For the quantitative analysis of receptor binding, we measured the simple target to non-target ratio, with the frontal cortex as a reference region. This ratio method was applicable to 2'-ISP because the kinetic analysis in normal subjects demonstrated a gradual decrease in radioactivity in basal ganglia after I hour, and the basal ganglia to frontal cortex ratio (BG/FCX) was stable at between 2 and 4 hours.9 This pseudo-equilibrium condition allows to use the simple BG/FCx ratio as a semiquantitative parameter of receptor binding. The cerebellum has been frequently used as a reference region for the analysis of D2 receptor binding in PET studies,15 but it is not suitable for SPECT studies because SPECT values in the cerebellum may not be accurate due to significant attenuation of the head holder. In contrast to NMSP, the binding of 2'-ISP in serotonin receptors is negligible and the cerebral cortex can be used as a non-specific binding site.2.9 In addition to the two classical subtypes of dopamine receptors, recent studies with a molecular genetic technique have revealed more subtypes, such as D3, D4 and D5 receptors. The affinity of 2'-ISP for these subtypes has not been investigated. 

The BG/FCx ratio of 2'-ISP demonstrated an age dependent decrease. The target to non-target ratios were similar to those obtained with other SPECT ligands,9,11 but obviously lower than the PET results.15 This was partly due to the physical limitations of the SPECT measurement such as lower spatial resolution and greater fraction of scattered radiation, but the characteristics of 2'-ISP itself may also be responsible for this. The instability of 2'-ISP causes the accumulation of a fairly large amount of radioactivity in the extracranial soft tissues and salivary glands as demonstrated in the coronal section of the SPECT images (Fig. 5). Even normal subjects sometimes showed a side-to-side difference in the uptake and distribution pattern in the basal ganglia, probably due to the poor image quality of the SPECT images. Moreover, very little radioactivity in the reference region results in a large variation among the normal subjects. These limitations results in a large variation in the BG/FCx ratio, and the reduced binding of 2'-ISP could not be clearly separated from the normal values in the present study. More careful kinetic analysis may be necessary to obtain better quantification.16 

In summary , the preliminary clinical data demonstrated the feasibility of dopamine D2 receptor imaging with SPECT, but more extensive efforts, including both the development of tracers with better characteristics and technical improvement in the quantitative analysis, are needed for clinical use of this method. 

ACKNOWLEDGMENTS 

The authors thank Mr. Toru Fujita for his valuable technical assistance. This work was supported in part by a Research Grant for Nervous and Mental Disorders from the Japan Ministry of Health and Welfare, and a Grant-in-aid for Scientific Research from the Japan Ministry of Education, Science and Culture. 

REFERENCES 

1. Kung HF. Ohmono Y, Kung M-P. Current and future radiopharmaceuticals for brain imaging with single photon emission computed tomography. Sem Nucl Med 20: 290-302, l990. 
2. Nakatsuka I, Saji H, Shiba K, Shimizu H, Okuno M, Yoshitake A, et al. In vitro evaluation of radioiodinated butyrophenones as radiotracers for dopamine receptor study. Life Sci 41 : 1989-1997, 1987. 
3. Saji H, Nakatsuka I, Shiba K, Tokui T. Horiuchi K, Yoshitake A, et al. Radioiodinated 2'-iodospiperone: a new radioligand for in vivo dopamine receptor study. Life Sci 41: 1999-2006, 1987. 
4. Iwasaki Y, Yonekura Y, Saji H, Nishizawa S. Fukuyama H, Iida Y, et al. SPECT imaging of dopamine D2 receptors in normal human brain with 2'-iodospi perone. J Nucl Med 36: 1191-1195, 1995. 
5. Wagner HN, Burns DH, Dannals RF, Wong DF, Langstrom B, Duelfer T, et al. Imaging dopamine receptors in the human brain by positron tomography. Science 221 : 1264-1266, 1983. 
6. Farde L, Hall H, Ehrin E. Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231 : 258-261, 1986. 
7. Saji H, Iida Y, Magata Y, Yonekura Y, Iwasaki Y, Sasayama S, et al. Preparation of 123I-labeled 2'-iodospiperone and imaging of D2 dopamine receptors in the human brain using SPECT. Nucl Med Biol 19: 523-529, 1992. 
8. Yonekura Y, Fujita T, Nishizawa S, Mukai T. Koide H, Yamamoto K, et al. Multidetector SPECT scanner for brain and body: system performance and applications. J Comput Assist Tomogr 13: 732-740, 1989. 
9. Brucke T, Podreka l, Angelberger P, Wenger S, Topitz A, Kufferle B, et al. Dopamine D2 receptor imaging with SPECT: studies in different neuropsychiatric disorders. J Cereb Blood Flow Metab 11 : 220-227, 1991. 
10. Baron JC, Maziere B, Loc'h C. Cambon H, Sgouropoulos P, Bonnet AM, et al. Loss of striatal [76Br]bromospiperone binding sites demonstrated by positron emission tomograph y in progressive supranuclear palsy. J Cereb Blood Flow Metab 6: 131-136, 1986. 
11. Chabriat H, Levasseur M, Vidailhet M. Loc' h C, Maziere B, Bourguignon MH, et al. In-vivo SPECT imaging of D2 receptor with iodine-iodolisuride: result in supranuclear palsy. J Nucl Med 33: 1481-1485, 1992. 
12. Muhr C, Bergstrom M, Lundberg PO. Bergstrom K. Hartvig P, Lundqvist H, et al. Dopamine receptors in pituitary adenomas: PET visualization with 11C-N-methylspiperone. J Comput Assist Tomogr 10: 175-180, 1986. 
13. Serri O. Marchisio AM, Collu R. Hardy J, Somma M. Dopaminergic binding sites in human pituitary adenomas other than prolactinomas. Horm Res 19: 97-102, 1984 
14. Ramsdell JS, Bethea CL, Jaffe RB, Wilson CB, Weiner RI. Characterization of dopamine and a-adrenergic receptors in human prolactin-secreting adenomas with (3H)-dihydroergocriptine. Neuroendocrinology 40: 518-525, 1985. 
15. Wong DF, Wagner HN Jr, Dannals RF, Links J, Frost JJ, Ravert HT, et al. Effects of age on dopamine and serotonin receptors measured by positron emission tomography in the living human brain. Science 226: 1393-1396, 1984. 
16. Laurelle M, van Dyck C. Abi-Dargham A, Zea-Ponce Y, Zoghbi SS, Charney DS, et al. Compartmental modeling of iodine-123-iodobenzofuran binding to dopamine D2 receptors in healthy subjects. J Nucl Med 35: 743-754, 1994.