Analysis of [18F]altanserin PET data
[18F]altanserin is the most used PET radioligand for studying serotonin 5-HT2A receptors. 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:
and Meltzer et al (1998), Bailer et al (2004), and Soloff et al. (2014) reported BPND:
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; Marner et al., 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 (Martin 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 version 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).
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
In rats blood-to-plasma ratio was initially 0.56±0.06, increasing to 0.62±0.05 at 180 min (Kroll et al., 2013).
Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, Madsen K, Frokjaer V, Martiny L, Paulson OB, Knudsen GM. A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: Normative data and relationship to physiological and demographic variables. Neuroimage 2004; 21: 1105-1113.
Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, McConaha CW, Henry SE, Brooks-Achenbach S, Barbarich NC, Kaye WH. Altered 5-HT2A receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness. Neuropsychopharmacology 2004; 29(6): 1143-1155.
Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, Lotstra F. Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography. Eur J Nucl Med. 1994; 21(9): 937-946.
Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J. Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 1997; 171: 444-448.
Erritzoe D, Frokjaer VG, Haugbol S, Marner L, Svarer C, Holst K, Baaré WF, Rasmussen PM, Madsen J, Paulson OB, Knudsen GM. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use. Neuroimage 2009; 46: 23-30.
Ettrup A, Svarer C, McMahon B, da Cunha-Bang S, Lehel S, M&oslahs;ller K, Dyssegaard A, Ganz M, Beliveau V, Jørgensen LM, Gillings N, Knudsen GM. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36: test-retest reproducibility and head-to-head comparison with the antagonist [18F]altanserin. Neuroimage 2016; 130: 167-174.
Frank GK, Kaye WH, Meltzer CC, Price JC, Greer P, McConaha C, Skovira K. Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biol Psychiatry 2002; 52(9): 896-906.
Frokjaer VG, Erritzoe D, Madsen J, Paulson OB, Knudsen GM. Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT2A receptor binding. Neuroscience 2009; 163: 640-645.
Frokjaer VG, Erritzoe D, Juul A, Nielsen FA, Holst K, Svarer C, Madsen J, Paulson OB, Knudsen GM. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding. Psychoneuroendocrinology 2010; 35(9): 1311-1320.
Hasler F, Kuznetsova OF, Krasikova RN, Cservenyak T, Quednow BB, Vollenweider FX, Ametamey SM, Westera G. GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies. Appl Radiat Isot. 2009; 67(4): 598-601.
Haugbøl S, Pinborg LH, Arfan HM, Frøkjær VM, Madsen J, Dyrby TB, Svarer C, Knudsen GM. Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 2007; 34: 910-915.
Hautzel H, Müller HW, Herzog H, Grandt R. Cognition-induced modulation of serotonin in the orbitofrontal cortex: a controlled cross-over PET study of a delayed match-to-sample task using the 5-HT2a receptor antagonist [18F]altanserin. Neuroimage 2011; 58(3): 905-911.
Herth MM, Knudsen GM. Current radiosynthesis strategies for 5-HT2A receptor PET tracers. J Labelled Comp Radiopharm. 2015; 58(7): 265-273.
Hurlemann R, Boy C, Meyer PT, Scherk H, Wagner M, Herzog H, Coenen HH, Vogeley K, Falkai P, Zilles K, Maier W, Bauer A. Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia. Anat Embryol. 2005; 210: 519-523.
Hurlemann R, Matusch A, Kuhn K-U, Berning J, Elmenhorst D, Winz O, Kolsch H, Zilles K, Wagner M, Maier W, Bauer A. 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology 2008; 195: 579-590.
Kroll T, Elmenhorst D, Matusch A, Wedekind F, Weisshaupt A, Beer S, Bauer A. Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. Mol Imaging Biol. 2013; 15: 456-467.
Kroll T, Elmenhorst D, Matusch A, Celik AA, Wedekind F, Weisshaupt A, Beer S, Bauer A. [18F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT2A receptor densities in the rat brain. Nucl Med Biol. 2014; 41: 1-9.
Larisch R, Klimke A, Hamacher K, Henning U, Estalji S, Hohlfeld T, Vosberg H, Tosch M, Gaebel W, Coenen HH, Müller-Gärtner H-W. Influence of synaptic serotonin level on [18F]altanserin binding to 5HT2 receptors in man. Behav Brain Res. 2003; 139(1-2): 21-29.
Lopresti B, Holt D, Mason NS, Huang Y, Ruszkiewicz J, Perevuznik J, Price J, Smith G, Davis J, Mathis C. Characterization of the radiolabeled metabolites of [18F]altanserin: implications for kinetic modeling. In: Quantitative Functional Brain Imaging with Positron Emission Tomography, 1998, p 293-298.
Marner L, Knudsen GM, Haugbøl S, Holm S, Baaré W, Hasselbalch SG. Longitudinal assessment of cerebral 5-HT2A receptors in healthy elderly volunteers: an [18F]-altanserin PET study. Eur J Nucl Med Mol Imaging 2009; 36(2): 287-293.
Marner L, Knudsen GM, Madsen K, Holm S, Baaré W, Hasselbalch SG. The reduction of baseline serotonin 2A receptors in mild cognitive impairment is stable at two-year follow-up. J Alzheimers Dis. 2011; 23(3): 453-459.
Martín A, Szczupak B, Gómez-Vallejo V, Plaza S, Padró D, Cano A, Llop J. PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2013; 33: 1967-1975.
Meltzer CC, Smith G, Price JC, Reynolds III CF, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST. Reduced binding of [18F]altanserin to serotonin type 2A receptord in aging: persistence of effect after partial volume correction. Brain Res. 1998; 813: 167-171.
Moses-Kolko EL, Price JC, Shah N, Berga S, Sereika SM, Fisher PM, Coleman R, Becker C, Mason NS, Loucks T, Meltzer CC. Age, sex, and reproductive hormone effects on brain serotonin-1A and serotonin-2A receptor binding in a healthy population. Neuropsychopharmacology 2011; 36(13): 2729-2740.
Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM. 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev. 2013; 33(1): 54-111.
Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, Madsen J, Knudsen GM. Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab. 2003; 23: 985-996.
Pinborg LH, Arfan H, Haugbol S, Kyvik KO, Hjelmborg JV, Svarer C, Frokjaer VG, Paulson OB, Holm S, Knudsen GM. The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined. Neuroimage 2008; 40: 1175-1180.
Price JC, Lopresti B, Mason NS, Huang Y, Holt D, Smith GS, Mathis CA. [18F]Altanserin PET studies of serotonin-2A binding: examination of nonspecific component. In: Quantitative Functional Brain Imaging with Positron Emission Tomography, 1998, p 427-434.
Price JC, Lopresti BJ, Mason NS, Holt DP, Huang Y,Mathis CA. Analyses of [18F]altanserin bolus injection PET data. I: Consideration of radiolabeled metabolites in baboons. Synapse 2001a; 41: 1-10.
Price JC, Lopresti BJ, Meltzer CC, Smith GS, Mason NS, Huang Y, Holt DP, Gunn RN, Mathis CA. Analyses of [18F]altanserin bolus injection PET data. II: Consideration of radiolabeled metabolites in humans. Synapse 2001b; 41: 11-21.
Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C, Hermanne JP, Guillaume M, Cantineau R, Comar D, Franck G. Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]altanserin: results in young normal controls. J Cereb Blood Flow Metab. 1995; 15: 787-797.
Smith GS, Price JC, Lopresti BJ, Huang Y, Simpson N, Holt D, Mason NS, Meltzer CC, Sweet RA, Nichols T, Sashin D, Mathis CA. Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. Synapse 1998; 30(4): 380-392.
Soloff PH, Price JC, Meltzer CC, Fabio A, Frank GK, Kaye WH. 5HT2A receptor binding is increased in borderline personality disorder. Biol Psychiatry 2007; 62: 580-587.
Soloff PH, Chiappetta L, Mason NS, Becker C, Price JC. Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder. Psychiatry Res. 2014; 222(3): 140-148.
Staley JK, Van Dyck CH, Tan PZ, Al Tikriti M, Ramsby Q, Klump H, Ng C, Garg P, Soufer R, Baldwin RM, Innis RB. Comparison of [18F]altanserin and [18)F]deuteroaltanserin for PET imaging of serotonin2A receptors in baboon brain: pharmacological studies. Nucl Med Biol. 2001; 28: 271-279.
Tan P-Z, Baldwin RM, van Dyck CH, Al-Tikriti M, Roth B, Khan N, Charney DS, Innis RB. Characterization of radioactive metabolites of 5-HT2A receptor ligand [18)F]altanserin in human and rodent. Nucl Med Biol. 1999; 26: 601-608.
van Dyck CH, Tan PZ, Baldwin RM, Amici LA, Garg PK, Ng CK, Soufer R, Charney DS, Innis RB. PET quantification of 5-HT2A receptors in the human brain: A constant infusion paradigm with [18F]altanserin. J Nucl Med. 2000; 41: 234-241.
Created at: 2016-08-23
Updated at: 2016-08-31
Written by: Vesa Oikonen