The early diagnosis of extrapyramidal disorders, such as Parkinson Disease, requires specific functional imaging , different from conventional brain functional imaging, which is related to an assessment of regional cerebral blood flow. Kung et al have developed derivatives of Tropanes labeled with Tc99m to demonstrate the distribution of the Dopamine transporter (1,2,4). The human transporter of Dopamine (DAT) a member of the family of NA+ , CL- dependent transporters, mediates the uptake of Dopamine into the Dopaminergic neuron by an electrogenic NA+ and CL- transport coupled mechanism. Dopamine and other reuptake blockers, such as cocaine and cocaine analogues bind to both shared and separate domains of the transporter, which can be dramatically influenced by the presence of cations.

The re-uptake of free Dopamine from the sinapsis cleff is the principal mechanism of modulation of dopaminergic function, and can be blocked by neurotoxics such as cocaine. This explains the stimulating dopaminergic effect of this drug, and conversly , the diminution of the transporter of Dopamine, that is observed early in Parkinson disease and explains the loss of the dopaminergic motor functions characteristic of this extrapyramidal disorder.

Radiopharmaceutical. Tc99m Tropane (Trodat 1) is labeled with Tc99m as per techniques reported by Kung et al (1) and Mozley et al (5) which consists of the labeling of the compound delivered in the form of Kit, with 50mCi of Tc99m ( 1850 MBq) and heating for 30 minutes at 120° .C. This is followed by an intravenous injection and acquisition of brain images 4 hours later.

The images are gathered with a single head SPECT SMV DSX system (Twinsburg, Ohio, USA) and High Resolution Fan Beam collimator. The images are reconstructed by Back Projection and there is no attenuation correction applied. The acquisition matrix is 64 x 64 .The three dimensional images are displayed as transaxial, coronal and sagital slides.

Patients. We present results in:

A) a normal control, a woman 65 years of age,

B) a patient 69 years old, male (FM) with bilateral Parkinson Disease of 10 years of evolution. The clinical presentation fluctuates between a level 2 and 5 (maximum incapacity during periods of akinesia), with a score of Hoehn and Yahr, with a UPDRS I =0 ,UPDRS III = 23 during ON and 86 during OFF, denoting severe symptomatology and with UPDRS IV=8 for collateral effects of L Dopa.

C) a patient, male of 50 years of age (AB) with an evolution of 2 ½ years with Right Hemiparkinsonism ( that presents in right upper and lower extremities) and with UPDRS I= 0, UPDRS III = 8 which means a moderate symptomatology.The patient has not received L-Dopa during his evolution. (De Novo Patient), UPDRS IV= 0.

RESULTS: The NeuroSPECT examination of the normal control demonstrates maximum concentration of the Dopamine Transporter in both caudate nuclei and putamen that stands out in contrast with poor relative uptake of the radiopharmaceutical in non-specific receptors of the brain cortex. Figure 1. The NeuroSPECT of patient SM with a 10 years of clinical course and marked fluctuating symptomatology demonstrates minimal uptake of Trodat-1 Tc99m in both caudate nuclei and both putamens. Figure 2. The intensity of uptake appears of lesser magnitud than the one observed in non-specific structures in the cortex. In the patient of hemiparkinsonism of right upper and lower extremities (AB) there is moderate impairment of uptake in the left caudate nucleus denoting reduction of the DAT concentration and maximal reduction in the left putamen. Furthermore, there is slight increased uptake of Trodat Tc99m. in the right caudate nucleus while there is diminution also of uptake in the right putamen Figure 3.

Figure 1(click=zoom) Figure 2 (click=zoom) Figure 3 (click=zoom)

The availability of a radiopharmaceutical that labels the transporter of Dopamine with Tc99m is a definite logistic advantage over agents that are labeled with I-123, a short-lived radionucleide (2,3). This is particularly true in our Latin-American environment because I-123 is not available for imagenology in Neurosciences. Furthermore, it is also economically impractical. for most of the Latin-American scientific centers. The agent developed by Kung et al (1) at the University of Pennsylvania, Philadelphia, USA and distributed in form of Kit by the Institute of Nuclear Energy Research, Taiwan is a successful solution to providing the possibilities of performing early diagnosis of Parkinson disease. We have observed a sensitive, early disminution of the uptake of Trodat- 1 preferentially in putamen, contralateral to the affected side of the patient.

The sharp contrast observed between the findings of the normal subject versus the advanced Parkinson disease and also the unilateral Parkinson disease offers the possibility of this type of imaging being useful for the early diagnosis of Parkinson disease. Conventional NeuroSPECT imaging, using agents that measure brain blood flow is not impaired in patients of Parkinson disease without dementia..(12). For this reason the radiopharmaceutical products Trodat- 1 Tc99m is highly promising for the study of Parkinson´s Disease.

BIBLIOGRAPHY

1.- Kung M-P, Stevenson DA, Plössl K, Meegalla SK, Beckwith A, Essman WD, Mu M, Lucki I, Kung HF. (^99m Tc) TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent. Eur J Nucl Med 1997; 24: 372-380.

2.- Kung M-P, Plössl K, Meegalla SK, Kung HF, A kit formulation fot the preparation of (^99m Tc) TRODAT-1: a new dopamine transporter imaging agent (abstract IV-23). Proe XIIth Intl Symp Radiopharm Chem, Uppsala, Sweden 1997: 263-265.

3.- Kung HF, Kim H-J, Kung M-P, Meegalla SK, Plössl K, Lee H-K. Imaging of dopamine transporters in humans with technetium-99m TRODAT-1. Eur J Nucl Med 1996; 23: 1527-1530.

4.- Dresel SHJ, Kung M-P Plössl K, Meegalla SK, Kung HF. Pharmacological effects of dopaminergic drugs on in vivo binding of (^99m Tc) TRODAT-1 to the central dopamine transporters in rats. Eur J Nucl Med 1998; 21: 31-39.

5.- Mozley P, Stubbs J, Plössl K, Dresel S, Barraclough E, Alavi A, Araujo L, Kung H. The biodistribution and dosimetry of a (^99m Tc) labeled tropane for imaging dopamine transporters journal of Nuclear Medicine 1998; 39: 2069-2076.

6.- Carroll FI, Rahman MA, Abraham P, Parham K, Lewis AH, Dannals RF, Shaya E, Scheffel U, Wong DF, Boja JW, Kuhar MJ. (¹²³I) 3B- (4-iodophenyl) tropan, 2B-carboxylic acid methyl ester (RTI-55), a unique cocaine receptor ligand for imaging the dopamine and serotonin transporters in vivo. Med Chem Res 1991; 1: 289-294.

7.- Stefan HJ Dresel, Mei-Ping T. Kung, XiaoFeng Huang, Karl Plössl, Catherine Hou, Chyng I. Shieue, Joel Karp, Hank F, Kung. In vivo imaging of serotonin transporters with (^99m Tc) TRODAT-1 in nonhuman primates Eur J Nucl Med (1999) 26: 342-347.

8.- Reith ME, Xu C, Chen NH. (1997) Pharmacology and regulation of the neuronal dopamine transporter. Eur J. Pharmacol, 324, 1-10.

9.- Gordon Y, Weizman R, Rehavi M (1996) Modulatory effect of agents active in the presynaptic dopaminergic system on the striatal dopamine transporter. Eur J Pharmacol, 298, 27-30.

10.- Giros B, Caron MC. (1993) Molecular caracterization of the dopamine transporter. TIPS, 14, 43-49.

11.- Miller GV, Staley JK et al. Inmunochemical analysis of dopamine transporter protein in Parkinson’s Disease. (1997) Ann Neurol, 41, 530-539.

12.- Miller B.L.,Cummings J.L., Mena I., Darcourt J. Neuroimaging in Clinical Practice: Comprehensive Textbook of Psychiatry: Kaplan H. Sadock B.J. Williams&Wilkins publishers Volume 1, Section 2.10:257-275 (1995).