Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats

In developing iodine-123-labelled amino acid derivatives for imaging cerebr al gliomas by single-photon emission tomography (SPET), we compared p-[I-12 3]iodo-L-phenylalanine (IPA), L-[I-123]iodo-1,2,3,4-tetrahydro-7-hydroxyiso quinoline-3-carboxylic acid (ITIC) and L-3-[I-123]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T386s cell s, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the I-123-iodinated agents for use as SPET radiopharmaceutica ls was evaluated in healthy experimental rats as well as in rats with stere otactically implanted C6 gliomas, The radiopharmaceutical uptake into gliob lastoma cells was rapid, temperature and pH dependent, and linear during th e first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onward s. The radioactivity concentration in glioma cells following 30-min incubat ion at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity p er million cells (ITIC < IMT less than or equal to IPA). Competitive inhibi tion experiments using alpha-(methylamino)-isobutyric acid and 3-amino-2-no rbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transpo rted by system ASC, indicated that IPA, like LMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of th e A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analy sis of uptake under conditions that change the cell membrane potential, i.e . in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of v alinomycin or nigericin induces a slight increase or decrease in the radiop harmaceutical uptake, suggesting a minor contribution of the mitochondria i n the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereaf ter showed efflux from the brain. The radioactivity concentration in health y rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactical ly implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 m in p.i.), with tumour-to-background ratios greater than 4. These data indic ate that IPA and ITIC, like IMT, exhibit interesting biological characteris tics which hold promise for in vivo brain tumour investigations by SPET.