L-Boronophenylalanine (L-BPA) is one of the 10B carriers used in boron neutron capture therapy (BNCT) in cancer treatment. L-BPA has been labelled with 18F (4-Borono-2-18F-fluoro-l-phenylalanine, [18F]FBPA) for diagnosis and to to allow assessment of tissue kinetics of L-BPA non-invasively (Ishiwata et al., 1991a, 1991b, 1992, 2018; Vähätalo et al., 2002). [18F]FBPA could also be used to select patients that would benefit from BNCT (Morita et al., 2018), and after BNCT, differentiate tumour recurrence from radiation necrosis (Beshr et al., 2018). The effective dose from [18F]FBPA PET study is similar than that of [18F]FDOPA and smaller than that of [18F]FDG (Sakata et al., 2013; Kono et al., 2017).
As an amino acid analogue, L-BPA is actively taken up by most tissues. In rapidly proliferating tissue, such as tumours, uptake is accelerated. Thus it is possible to achieve good contrast in 10B concentration between malignant and normal tissue by using L-BPA as carrier. Imahori et al (1998a) detected tumour-to-normal tissue ratios of around 3 for glioma patients, with equilibrium between tumour and normal tissue after 20 min. Chadha et al (1998) achieved an average tumour-to-blood (T/B) ratio of 3.5 with BPA-fructose complex; the 10B concentration in normal brain was smaller than that in blood. Mallesch et al (1994) detected average T/B ratios of 4.4±3.2 in metastatic melanoma (n=12) and 2.2±1.2 in glioma (n=6) using D,L-BPA-fructose. Uptake is high also in normal tissues with active protein synthesis, including salivary glands (Kabalka et al., 2003; Ariyoshi et al., 2011).
In the transport step from plasma to cells, [18F]FBPA prefers LAT1 over LAT2, and therefore tumour imaging using [18F]FBPA and BNCT using L-BPA does not suffer from the inflammation-induced increase in amino acid uptake (Wittig et al., 2000; Detta and Cruickshank, 2009; Yoshimoto et al., 2013; Wongthai et al., 2015; Watabe et al., 2017a). Intracellular boron accumulation is affected by intracellular amino acid concentration, which could possibly be controlled for BNCT (Sato et al., 2014). In brain tumours, disruption of blood-brain barrier enhances the delivery of L-BPA and [18F]FBPA (Barth et al., 1997, 2000, and 2002; Yang et al., 2000; Hsieh et al., 2005; Yang et al., 2014; Wu et al., 2014). Similarity in pharmacokinetics between fluorine-18-labelled and non-labelled L-BPA has been demonstrated (Imahori et al., 1998b; Wang et al., 2004; Hanaoka et al., 2014; Watanabe et al., 2016), and intracellular distribution is similar (Chandra et al., 2002). The accumulation of [18F]FBPA has been found to correlate with the degree of malignancy (Imahori et al., 1998a). The L form of the radiopharmaceutical is taken up better than the racemic D,L-mixture. Hypoxia may reduce the uptake of BPA (Wada et al., 2018).
Since 10B and 11B are detectable with magnetic resonance, the kinetics of racemic BPA and L-BPA have been also assessed in MRI studies, mainly in animal models (Ishiwata, 2019).
[18F]FBPA is not incorporated into proteins, except in melanoma it may be involved in melanogenesis and 18F is then trapped in melanin (Ishiwata et al., 1992; Kubota et al., 1993). In the liver, [18F]FBPA may be converted to 2-[18F]fluoro-l-tyrosine (Ishiwata, 2019), which can be incorporated into proteins, including plasma proteins that are released into blood (Coenen et al., 1989). Borate group can be slowly cleaved from L-BPA in humans (Bendel et al., 2010).
Appearance of label-carrying metabolites in plasma is negligible in mice (Ishiwata et al., 1991b; Grunewald et al., 2017) and humans (Imahori et al., 1998c; Havu-Aurén et al., 2007; Isohashi et al., 2016), and any metabolite correction can be considered unnecessary.
Fraction of protein-bound radioactivity increases with time in mice (Ishiwata et al., 1991b), which may be caused by 18F-containing plasma proteins released from the liver.
Plasma and blood TACs measured from samples collected during PET scanning can be converted to each other based on the ratio of activities in red blood cells and plasma, using p2blood and b2plasma. The ratio has been determined from ten patients earlier (unpublished), and RBC-to-plasma ratio rises from zero with a slope of 0.00888 min-1. Alternatively, a constant factor 1.3 has been used to convert blood curve to plasma (Imahori et al., 1998b).
Imahori et al (1998a and 1998b) used a three-compartmental model for the evaluation of kinetics of [18F]FBPA. Parameter k4 was omitted because of its minimal significance. Accumulation of [18F]FBPA was mainly determined by K1 (dependent on LAT-1), and k3 did not correlate with malignancy (Imahori et al., 1998a). The K1-k4 model has also been applied to rat data (Chen et al., 2004).
Kabalka et al (1997) used a four-compartment model for kinetic analysis of [18F]FBPA-fructose. This model differs from the three-compartment model by an additional blood-pool compartment that represents protein binding and uptake in red blood cells as well as the appearance of possible metabolites in the whole blood. Model parameters were used to estimate the optimal irradiation time window for effective 10B-BPA BNCT by simulating tissue curves for continuous infusion of [18F]FBPA (Kabalka et al., 1997; Takahashi et al., 2003; Koivunoro et al., 2015). The simulation/extrapolation approach may provide better BNCT dose estimates than assuming constant tumour-to-blood ratios (Koivunoro et al., 2015). However, [18F]FBPA PET studies are usually conducted in tracer conditions or at least with markedly lower mass of L-BPA that what is used in actual BNCT. Therefore the rate constants may not be representative in the saturating conditions of the BNCT.
In benign neoplasms tissue uptake reaches its peak already 3-5 min after injection, suggesting that a two-compartmental model (one tissue compartment) could be used to describe the data (Havu-Aurén et al., 2007). Similar phenomenon has been seen in many tumours of the head and neck cancer, but in malignant melanomas the three compartmental model (with or without k4) is required (Ishiwata, 2019).
Patlak and Logan analysis
Imahori et al (1998a) found positive slope with multiple-time graphical analysis for irreversible uptake (Patlak plot), suggesting the involvement of one-way transfer and accumulation of the radiopharmaceutical, and the results correlated well with the rate constants from compartmental model fitting. [18F]FBPA PET studies with arterial input function have also been analysed using FUR ("incorporation constant").
In our hands, Patlak plots have provided clear positive slopes in tumour tissue, with flat lines in normal tissues. Logan plot in normal tissue provides similar distribution volumes that can be calculated from the rate constants of reversible three-compartmental model.
Tissue-to-reference tissue ratio (SUV ratio) and tissue-to-plasma ratio are simple analysis methods often used to analyse [18F]FBPA PET data (Ishiwata, 2019). Blood activity can be assessed from ROI drawn on the left ventricle of the heart (Isohashi et al., 2016).
Ratios are particularly well-suited for BNCT, since high 10B tumour-to-background ratio is essential in BNCT to limit the radiation damage to the healthy tissues. Organ-to-plasma ratio of 10B correlates well with the organ-to-plasma ratio of 18F (Grunewald et al., 2016; Yoshimoto et al., 2018), applying also to tumour-to-blood and tumour-to-normal tissue ratios (Nariai et al., 2009; Morita et al., 2018).
Shimosegawa et al (2016) and Watabe et al (2017b) calculated the 10B in organs (normal tissues) by simply multiplying the relative uptake of [18F]FBPA per g tissue by the therapeutic dose (g) of L-BPA, neglecting possible saturation effects from the much higher mass of the L-BPA dose.<-- -->
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Updated at: 2019-04-23
Created at: 2004-10-14
Written by: Vesa Oikonen