[18F]fluciclovine (anti-[18F]FACBC, [18F]GE-148, fluciclovine (18F), Axumin®, NMK36) is a synthetic leucine amino acid derivative, anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (or trans-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid). It was developed as an 18F-labelled alternative to earlier 11C-labelled radioligands (Shoup et al., 1999; Nye et al., 2007).
Tumour cells upregulate amino acid transport because of increased requirement of substrates for energy production and protein synthesis. The use of [18F]fluciclovine is approved in EU and USA for the detection of recurrent prostate cancer. Bone metastases in men with recurrent prostate cancer can be detected in early phase (Chau et al., 2018), and preoperative lymph node staging can be performed (Selnæs et al., 2018). Tracer has also shown promise in imaging of breast cancer (Liang et al., 2011; Tade et al., 2016; Ulaner et al., 2017), renal papillary cell carcinoma (Schuster et al., 2009), and gliomas (Tsuyuguchi et al., 2017; Parent et al., 2018).
[18F]fluciclovine is transported into cells by ASCT2 and LAT1. ASCT2 is sodium-dependent and LAT1 is sodium-independent transporter. LAT1 cannot actively increase the intracellular amino acid concentrations, but it exchanges its substrate amino acids between intra- and extracellular spaces. ASCT2 and LAT1 are overexpressed in several types of cancer. In primary prostate cancer [18F]fluciclovine uptake correlates with LAT1 but not with ASCT2 expression (Saarinen et al., 2019). Despite of [18F]fluciclovine being a leucine analogue, its uptake best resembles the uptake of glutamine. (Okudaira et al., 2011 and 2013; Ono et al., 2013 and 2015; Oka et al., 2014). It is not incorporated into proteins (Okudaira et al., 2011).
Related radioligands include syn-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (syn-[18F]FACBC) and anti-1-amino-2-[18F]fluorocyclobutane-1-carboxylic acid which are also avidly transported into cancer cells (Yu et al., 2009; Yu et al., 2010). Additionally, syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (syn-[18F]FMACBC and anti-[18F]FMACBC) have been synthesized and evaluated in rat models (Martarello et al., 2002).
[18F]fluciclovine can be transported across the blood-brain barrier, but its accumulation into normal or inflamed brain tissue is low. Instead, its uptake is high in gliomas, partially because of disrupted BBB, but uptake is increased also in gliomas with intact BBB (Doi et al., 2015). The tracer can be used to delineate the glioma spread that is undetectable with Gd contrast-enhanced T1-weighted MRI (Kondo et al., 2016).
[18F]fluciclovine has only low accumulation in granulocytes and macrophages, and can therefore usually separate tumours from inflammatory response better than [18F]FDG; however, uptake in T and B cells is significant (Oka et al., 2014).
Tracer has excellent in vivo stability; Asano et al (2011) did not find any label-carrying metabolites in the plasma, and also urine contains almost exclusively the parent tracer. Neither did Sörensen et al (2013) find any metabolites in the human blood samples, and only ∼1% in rats. Thus, correction for metabolites is not necessary.
Excretion of the tracer into urine is slow. Clearance from blood is still fast since tracer is quicly distributed into all tissues, including skeletal muscle, where the uptake continued to the end of the scan (Asano et al., 2011; Sörensen et al., 2013). Blood activity reaches a relatively stable level 10 min p.i. and after that decreases only slowly (Sörensen et al., 2013).
Sörensen et al (2013) measured the blood activity using continuous blood sampling system for the first 10 min, and took discrete blood and plasma samples for 90 or 120 min. Blood TAC was converted to plasma TAC using individually measured plasma/blood ratios, which are not mentioned in the publication.
Sörensen et al (2013) noted that the summed image for 1-15 min p.i. had the best tumour-to-background contrast, and they used it for clinical image review, VOI definition, and for calculating SUV. Tumour uptake was highest at ∼3 min. In muscle, uptake was slow and continued to increase over 90 min. In bone marrow the washout was slow.
[18F]fluciclovine is known not to be incorporated into proteins, and tissue uptake is related to reversible transport processes only. Sörensen et al (2013) applied both 1-tissue and 2-tissue reversible compartmental models to the data with arterial plasma as input function. The first tissue compartment was assumed to represent extracellular space, and the second tissue compartment the intracellular space. 1-tissue compartmental model fitted the data from tumours and normal tissues as well as the 2-tissue compartmental model, and the resulting volume of distribution, VT=K1/k2, was almost identical to the VT from Logan plot (Sörensen et al., 2013). In muscle VOIs, the K1 was ∼0.018 mL/(mL*min), and in tumour VOIs it was 0.101-0.271 mL/(mL*min); this match well the expected plasma flow to resting muscle and tumours, suggesting that K1 could be used as a surrogate marker for perfusion.
Volumes of distribution from Logan plot and compartmental model are almost identical (Sörensen et al., 2013). Saarinen et al (2019) applied Logan plot to PET studies of primary prostate cancer, using as input the image-derived blood curve from iliac artery.
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Updated at: 2019-06-13
Created at: 2018-09-12
Written by: Vesa Oikonen