Preferred Stereoselective Transport of the D-isomer of cis-4-[¹⁸F]fluoro-proline at the Blood–Brain Barrier

Abstract

Generally, L-amino acids are preferably transported into mammalian cells compared with their D-isomers, and only L-amino acids are incorporated into proteins. Former studies, however, indicated that D-[H]proline is accumulated in the brain of mice after injection, while L-[ 3 H]proline is not. We investigated the differential cerebral uptake of the D-and L-isomers of the PET tracer cis-4-in rats by dual tracer autoradiography and the uptake of D-cis-FPro in two human subjects by PET. The standardized uptake value (SUV) of D-cis-FPro in the cerebral cortex of rats 2 h p.i. was 3.0571.18 (n ¼ 9) versus 0.0670.01 (n ¼ 4) for L-cis-FPro (Po0.001) and 1.2970.27 (n ¼ 4) for D-Pro versus 0.3070.14 (n ¼ 9) for L-Pro (Po0.001). Analysis of the rat brain tissue after injection of D-cis-FPro (n ¼ 3) revealed no radioactivity in the proteins but a relevant part in the form of L-trans-FPro. The PET studies yielded a four-to five-fold higher SUV and influx rate constant in the human cortex for D-cis-FPro than for Lcis-FPro. We conclude that D-cis-FPro and D-Pro are preferably transported at the blood-brain barrier compared with their L-isomers and isomerized to the L-form within the brain. Thus, D-Pro in the plasma might be a source of intracerebral L-proline, which has been shown to act as a modulator of excitatory neurotransmission.

Detection of Secondary Thalamic Degeneration After Cortical Infarction Using cis-4-18F-Fluoro- D-Proline

“…Recently, we observed that the D-isomer of cis-18 F-FPro is transported across the BBB in contrast to L-cis- 18 F-FPro (7). Similar to this finding, an intensive labeling of the cerebral cortex has been reported after injection of D-3 Hproline in mice, whereas cortical uptake of L-3 H-proline was negligible (8).…”

“…Thus, some metabolic degradation of the tracer and uptake of metabolites cannot be excluded. However, analysis of the brain homogenates of rats revealed that the entire radioactivity in the brain was due to free fluoroproline, indicating that the tracer signal in the brain is not caused by metabolites (7). In the area of the cortical infarction, the function of the BBB may be disturbed and a penetration of metabolites cannot be excluded.…”

“…Because we did not evaluate the influence of BBB disruption on tracer uptake, it cannot be excluded that radioactivity within the infarct area was influenced by passive diffusion of the tracer or its metabolites. D-cis-18 F-FPro, however, is able to penetrate the intact BBB and a disruption of the BBB is not a prerequisite for tracer accumulation (7).…”

“…We found a strong signal already at 3 d after infarction, whereas MRI and PET using 11 C-PK11195 were unable to detect thalamic involvement at this stage. In contrast to 11 C-PK11195, which has been used in many PET studies, D-cis- 18 F-FPro fulfills all requirements for widespread clinical application, including efficient radiosynthesis, 18 F labeling with a 109-min half-life, and suitable tracer kinetics for brain imaging (7).…”

The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

“…On the other hand, Dalanine and D-leucine levels are elevated in the cerebral cortex of ddY/DAO-mice by a similar magnitude to that in the cerebellum. This pattern of results in the ddY/DAO-mouse illustrates the fact that there is more to the metabolism of brain D-amino acids than just locally acting DAO-potentially including selective D-amino acid uptake into the brain, 58,63,64 other enzymes and transporters (which may differ in their selectivity for different D-amino acids, and in their distribution within the brain), and a role of peripheral as well as central actions of DAO.…”