Positron-labeled DOPA analogs to image dopamine terminals

Altered dopamine function has been implicated in disorders such as Parkinson's disease (PD) and other motor disorders, schizophrenia, substance abuse, attention deficit disorder, and other neuropsychiatric diseases. A useful approach to the development of PET imaging agents for dopamine terminals is to target the enzymes involved in dopamine biosynthesis. Tyrosine hydroxylase (TH) converts dietary L-p-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the first and rate-limiting step in dopamine synthesis. Thus, a TH-targeted imaging agent would be the ideal PET tracer of dopamine neuronal activity. However, efforts to develop TH-based tracers have so far been unsuccessful. The next enzyme in dopamine synthesis is aromatic L-amino acid decarboxylase (AAAD), which converts L-DOPA to dopamine. AAAD was the first target in the development of imaging agents for dopamine neurons. The first useful AAAD PET tracer was 6-[F-18]Fluoro-L-DOPA (FDOPA). Later, a practicable synthesis of L-[beta-C-11]DOPA was developed. However, the adherence of these tracers to all the catabolic pathways of L-DOPA has been a disadvantage because of the contributions of labeled metabolites to PET images. Thus, alternative tracers with simpler metabolism such as fluoro-L-m-tyrosine (FMT) have been developed. PET studies in nonhuman primates have suggested that FMT is the PET imaging agent of choice for AAAD-containing neurons. Initial human studies show that this marker is useful in the assessment of AAAD-related neuropsychiatric disorders. This article discusses the origins and validation of dopamine PET tracers and delineates the similarities and differences between therapeutic drug development and radiopharmaceutical development as exemplified by studies on the dopamine system. (C) 2003 Wiley-Liss, Inc.