Analysis of [18F]altanserin PET data
[18F]altanserin is the most used PET radioligand for studying serotonin 5-HT2A receptors in the brain. It provides excellent target-to-background ratio. However, due to more favourable radiometabolite profile, [18F]deuteroaltanserin has been proposed as an alternative PET tracer.
Altanserin has much higher affinity to 5-HT2A receptors (Ki 0.13 nM) than to α1-adrenoceptors (Ki 5 nM) or D2Rs (Ki 62 nM), suggesting that [18F]altanserin PET results can be attributed to 5-HT2A receptor binding (Paterson et al., 2013).
Gender, and hormonal contraception in women, does not affect [18F]altanserin binding (Frokjaer et al., 2009). Plasma estradiol levels correlate with 5-HT2AR binding in healthy males (Frokjaer et al., 2010). Body mass index correlates with the binding parameters, but not the use of alcohol or tobacco (Erritzoe et al., 2009). Binding pattern in the human brain is strongly genetically determined (Pinborg et al., 2008).
The lipophilic radiometabolite of [18F]altanserin contribute to the nonspecific binding (Smith et al., 1998; Tan et al., 1999; Price et al., 2001a and 2001b). Therefore a complex dual-input compartmental model was introduced; the simple Logan plot was shown to provide good correlation with the receptor densities, although the values were biased (Price et al., 2001a and 2001b; Larisch et al., 2003). For Logan plot, dynamic 90-min scans with arterial plasma sampling, plasma metabolite analysis, and cerebellum as reference region, have been used (Biver et al., 1994; Soloff et al., 2007; Moses-Kolko et al., 2011); Logan plot with metabolite corrected plasma input provides VT for the regions of interest and for the reference region (VND), and BPP is then calculated as
Logan plots are linear at least after 15 min p.i. (Sadzot et al., 1995). Meltzer et al (1998) fitted Logan plot data starting at 10 min p.i, Frank et al (2002) already at 8 min p.i., and Bailer et al (2004) from 12 min. Frank et al (2002) reported DVR instead of BPP:
In several studies both BPP and BPND have been reported.
DVR has also been estimated noninvasively using Logan plot with cerebellum as the reference input (Hurlemann et al., 2005). Hautzel et al (2011) have applied a multilinear model with activity in cerebellum as the input function to estimate BPND from 90-min dynamic data; model is related to the Logan plot with reference input.
Alternatively, bolus-plus-infusion method was shown to be able to correct for the effect of the BBB-penetrating radiometabolite (van Dyck et al., 2000). Adams et al (2004) scanned the subjects at 120-160 min after the initial bolus, and this protocol has thereafter been used in numerous [18F]altanserin studies. Two-hour scan time was shown to be sufficient to provide binding parameters with excellent test-retest reliability (Pinborg et al., 2003; Haugbøl et al., 2007). [18F]altanserin binding also remains relatively stable over at least two years in healthy individuals and patients with mild cognitive impairment (Marner et al., 2009; 2011). The sample size required to detect a 20% BPP difference in brain regions with high receptor density is approximately 27 (Haugbøl et al., 2007). Binding potential is calculated at steady-state from the metabolite-corrected plasma activity (CP), and specific activity in brain region (CVOI - CND, where CND is the activity inside VOI placed in cerebellum):
Biver et al (1994) compared three-tissue compartmental model, Logan plot, and ratio method (ROI/cerebellum - 1 at 60-90 min p.i.) in estimation of the binding potential k3/k4. For SPM analysis simple sum images (75-90 min p.i.) have been used (Biver et al., 1997).
Lipophilic metabolite does not hamper the rat studies (see below), simplifying the analyses. However, [18F]altanserin is a substrate of P-glycoprotein in rats; [18F]altanserin binding results will be biased, if P-gp expression is affected by the disease model (Kroll et al., 2014).
In [18F]altanserin rat studies dynamic 64-min PET scans were analyzed applying SRTM with cerebellum as the reference region (Martín et al., 2013). Kroll et al (2013) used a 180-min dynamic PET scan protocol with blood sampling and analyzed the data using several methods: VT was estimated with plasma input data applying two-tissue compartmental model with blood volume fixed at 3%, Logan plot, and a multilinear version of Logan plot; cerebellum as reference input was used to estimate the BPND applying Logan plot and several versions of SRTM. 150-min was found to be sufficient scan length in rats, and suitable analysis methods were 2TCM, multilinear version of plasma input Logan plot, and SRTM (Kroll et al., 2013).
SRTM can be used to assess changes in endogenous serotonin level (Ikoma et al., 2021).
Metabolism of [18F]altanserin in humans is relatively slow, with about 40-50% parent tracer in plasma 90 min after bolus injection (Smith et al., 1998; Hasler et al., 2009). Serotonin-releasing drug dexfenfluramine and hallucinogen psilocybin did not affect plasma metabolite fractions (Hasler et al., 2009). At least four radiometabolites can be found in plasma (Tan et al., 1999).
In rats the metabolism is even slower, with about 70% parent tracer in plasma after 3 hours; no lipophilic metabolites were found in rats (Kroll et al., 2013).
Plasma versus blood radioactivity concentration
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Updated at: 2021-12-06
Created at: 2016-08-23
Written by: Vesa Oikonen