Biological imaging and the molecular basis of dopaminergic diseases

The development and validation of preclinical biological probes of nigrostriatal dysfunction are part of the next frontier for battling diseases involving dopamine deficiency. In this work, the quantitative relationship relationship between radiofluorinated L-DOPA, [e.g., L-3,4-dihydroxy-6-[18F]fluorophenylalanine (6-[18F]fluoro-L-DOPA, FDOPA)] kinetics measured with positron emission tomography and central dopamine biochemistry is discussed. A hypothesis of a possible "non-linearity" of FDOPA kinetics with dopaminergic cell losses is presented to explain apparent discrepancies in post-mortem biochemical and histological determinations in Parkinson's disease. Similar observations have been made in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed monkeys and human subjects where the FDOPA uptake constantly fell within normal values unless severe nigral damage had occurred. The limitations of FDOPA, and other biological probes, for examining the asymptomatic phase of dopaminergic diseases and the future direction of research are discussed.