A selective PET or SPECT ligand for the presynaptic element of serotonin (5-HT) neurons has yet to be developed. Once available, such a ligand should greatly facilitate study of 5-HT function in the living human brain. It should also permit detection of subclinical 5-HT neural damage in human populations considered at risk [e.g., individuals exposed to neurotoxic amphetamine drugs such as 3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine]. During the past funding period, this laboratory has synthesized, radiolabeled and evaluated a series of compounds that held promise as selective presynaptic 5-HT PET/SPECT ligands. Compounds tested include several [11C]/[18F]-labeled paroxetine analogs, [11C]-labeled citalopram, fluoxetine, cis-N-,N-dimethyl-3-(2'4'-dichlorophenyl)-indanamine and [123I]-labeled RTI-55. Of these, only [123I]-RTI-55 was found to display sufficiently high specific in vivo binding to be considered useful for quantitative SPECT imaging. Preliminary in vitro and in vivo studies indicate that [123I]-RTI-55 labels the 5-HT transporter with high affinity and that it can be used to detect clinically silent damage of 5-HT neurons in rodents as well as nonhuman primates.
The specific aims of this proposal are to 1) develop a unilateral animal model of 5-HT neurotoxicity that will facilitate development of a presynaptic 5-HT PET/SPECT ligand; 2) confirm and extend preliminary studies showing that [123I]-RTI-55 is a promising SPECT ligand for labeling the 5-HT transporter in vivo; 3) use [123I]-RTI-55 to detect subclinical damage of 5-HT neurons induced by MDMA and fenfluramine in nonhuman primates; 4) label RTI-55 with [11C] for PET studies and compare the results with those obtained by SPECT using [123I]- labeled RTI-55 and 5) continued efforts to develop other [11C]/[18F]- labeled PET ligands that will label the 5-HT transporter more selectively than RTI-55 (which also labels the DA transporter). The long-term goals of this research are to develop novel SPECT/PET ligands which can serve as tools for investigating 5-HT function in the normal living human brain. In addition, this research seeks to develop methods for using such ligands to detect subclinical damage of 5-HT neurons in patient populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006309-04
Application #
3212969
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1989-09-30
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Scheffel, U; Szabo, Z; Mathews, W B et al. (1998) In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomography study in the living baboon brain. Synapse 29:183-92
Horti, A; Scheffel, U; Stathis, M et al. (1997) Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors. J Nucl Med 38:1260-5
Scheffel, U; Steinert, C; Kim, S E et al. (1996) Effect of dopaminergic drugs on the in vivo binding of [3H]WIN 35,428 to central dopamine transporters. Synapse 23:61-9
Szabo, Z; Kao, P F; Mathews, W B et al. (1996) Positron emission tomography of 5-HT reuptake sites in the human brain with C-11 McN5652 extraction of characteristic images by artificial neural network analysis. Behav Brain Res 73:221-4
Scheffel, U; Szabo, Z; Mathews, W B et al. (1996) Fenfluramine-induced loss of serotonin transporters in baboon brain visualized with PET. Synapse 24:395-8
Szabo, Z; Scheffel, U; Suehiro, M et al. (1995) Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652. J Cereb Blood Flow Metab 15:798-805
Szabo, Z; Kao, P F; Scheffel, U et al. (1995) Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652. Synapse 20:37-43
Scheffel, U; Kim, S; Cline, E J et al. (1994) Occupancy of the serotonin transporter by fluoxetine, paroxetine, and sertraline: in vivo studies with [125I]RTI-55. Synapse 16:263-8
Suehiro, M; Scheffel, U A; Ravert, H T et al. (1994) Highly potent indanamine serotonin uptake blockers as radiotracers for imaging serotonin uptake sites. Nucl Med Biol 21:1083-91
Suehiro, M; Scheffel, U; Ravert, H T et al. (1993) [11C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with PET. Life Sci 53:883-92

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