An Overview of PET Studies of the Cerebral Uptake of Amino Acids

Abstract

Molecular imaging with positron emission tomography (PET) has revolutionized the study of brain physiology. The facilitated diffusion of large neutral L-amino acids (LNAA) across the blood–brain barrier (BBB) is mediated by the LAT1 carrier in the capillary endothelium. A number of substrates for this carrier have been labeled with fluorine-18 and tested as PET oncology tracers; compounds such as [18F]fluoro-ethyltyrosine enter the brain, but are not metabolized. Over-expression of LAT1 and other transporter systems in some tumors results in elevated LNAA uptake relative to the physiological background. Dynamic PET with the endogenous LNAA [11C]tyrosine PET reveals not just reversible BBB transport but also irreversible trapping in brain protein, which can be quantified using linear graphic analysis. In theory, [11C]tyrosine PET might also reveal a signal related to the synthesis of dopamine in nigrostriatal terminals, but in practice, the neurotransmitter pathway cannot be visualized against the background of protein synthesis. However, the trapping of [18F]-fluorodopa (FDOPA) and other aromatic L-amino acid decarboxylase (AAADC) substrates reveals the integrity of the nigrostriatal dopamine pathway, without interference from a background of physiological protein synthesis. The serotonin precursor [11C]-5-hydroxytryptophan seems to be decarboxylated preferentially by AAADC expressed in serotonin fibers; in theory, specificity for visualizing the serotonin pathway is to be obtained with α-[11C]methyltryptophan ([11C]AMT), which is not a substrate for protein synthesis. However, the rate of conversion of this tracer to α-[11C]methyserotonin in serotonin neurons of living brain is low, such that its quantitation in PET studies is challenging. The issue of conversion is also central to prospects for molecular imaging of the kynurenine pathway in PET studies with [11C]AMT.