Analysis of [11C]MADAM
[C-11]MADAM is developed for imaging of serotonin transporter (SERT, 5-HTT) in living human brain. Biggest problem with SERT PET radioligands has been very low selectivity. In this sense MADAM seems to be a good tracer. All animal and human studies show that is has high affinity and selectivity to SERT. Chalon et al. (2003) state that MADAM has around 1000-fold better selectivity for the serotonin transporter than for other transporters.
In vitro rat studies with [3H]MADAM (Chalon et al. 2003) determined total binding in the absence of any drug and nonspecific binding in the presence of 10-6 paroxetine. Nonspecific binding was found to be around 15%. Cerebral binding values fit well with known serotonin transporter localization. Radioactivity was highest in dorsal raphe, superior colliculi, frontal cortex, and laterodorsal thalamic nuclei. Compared to other SERT ligands, binding was quite high in the frontal cortex and relatively low in the caudate putamen. Binding values of a post mortem human brain study roughly paralleled those of the rat study.
Compartment model analysis
For [3H]MADAM, a one-site model (single binding site) was suggested by Chalon et al (2003).
For [11C]MADAM, Lundberg et al. (2005) compared 3CM and 2CM models for 54 regions (9 subjects *6 brain regions) and found that the 3CM model (with fixed K1/k2) was superior to 2CM in 16 cases. Without fixing of K1/k2, the model gave unreliable results.
Binding potential can be calculated either directly from k3/k4 or indirectly from volumes of distribution (VT) as DVR-1 (Lundberg et. al. 2005).
Several publications on [11C]MADAM report that regional analysis has been done with SRTM, cerebellum as reference region (Henningsson et al. 2009; Jovanovic et al. 2009; Lundberg et al. 2006 and 2012; Schain et al., 2012; Takano et al. 2013; Tuominen et al. 2013 and 2014).
Lundberg et. al. (2005) verified the suitability of SRTM in analysis of [11C]MADAM data. Results of SRTM were similar to Logan plot and 3CM fitting.
Lundberg et. al. (2005) verified the suitability of Logan plot (with reference region input) in analysis of [11C]MADAM data. Results were similar to SRTM and 3CM.
Wavelet aided Logan plot has been used to compute parametric DVR images with cerebellum as reference region (Schain et al. 2013). Parametric images can be used to measure drug occupancy in humans (Stenkrona et al., 2013).
Transient equilibrium (ratio method)
Lundberg et al. have tested two versions of transient equilibrium (TE) model. For the first version BPND was calculated traditionally as the ratio of bound and free ligand in peak equilibrium time. In the second version, the ratio was taken from areas under the curve. It was found that TE gave underestimated results for raphe nucle region in comparison with SRTM, Logan plot and 3CM fitting (Lundberg et. al. 2005).
Cerebellum is considered have very low density of 5-HTT and thus suitable to be used as reference region (Lundberg et al. 2005). In more recent studies, cerebellar cortex is used as reference region (Majuri et al., 2017 and 2018).
It has been tested with 9 subjects [11C]MADAM data that 2-compartment model (2CM) fits cerebellum better than 3-compartment model (3CM) (Lundberg et al. 2005).
Metabolites in plasma
In the study of Lundberg et al (2005), two metabolites were found for [11C]MADAM and the Sigmoid function was found to fit best with fraction of unchanged tracer.
One of the metabolites, [11C]SOMADAM, appears rapidly in human plasma, and has very high affinity for SERT (Gourand et al., 2014). Due to its low quantities it does not complicate [11C]MADAM PET studies (Gourand et al., 2014).
Halldin C, Lundberg J, Sóvágó J, Gulyás B, Guilloteau D, Vercouillie J, Emond P, Chalon S, Tarkiainen J, Hiltunen J, Farde L. [11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET. Synapse 2005; 58(3): 173-183.
Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, Halldin C, Nordström AL. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage 2008; 39(3): 1408-1419.
Karlsson L, Tuominen L, Huotarinen A, Leppämäki S, Sihvola E, Helin S, Sipilä M, Tani P, Hirvonen J, Hietala J, Karlsson H. Serotonin transporter in attention-deficit hyperactivity disorder - preliminary results from a positron emission tomography study. Psychiatry Res. 2013; 212(2): 164-165.
Kauppinen TA, Bergström KA, Heikman P, Hiltunen J, Ahonen AK. Biodistribution and radiation dosimetry of [123I]ADAM in healthy human subjects: preliminary results. Eur J Nucl Med Mol Imaging 2003; 30(1): 132-136.
Lundberg J, Odano I, Olsson H, Halldin C, Farde L. Quantification of 11C-MADAM binding to the serotonin transporter in the human brain. J Nucl Med. 2005; 46(9): 1505-15.
Lundberg J, Halldin C, Farde L. Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study. Synapse 2006; 60(3): 256-63
Lundberg J, Borg J, Halldin C, Farde L. A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain. Psychopharmacology (Berl). 2007; 195(3): 425-433.
Lundberg J, Christophersen JS, Petersen KB, Loft H, Halldin C, Farde L. PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsychopharmacol. 2007; 10(6): 777-785.
Lundberg J, Tiger M, Landén M, Halldin C, Farde L. Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012; 15(8):1167-1172.
Maron E, Tõru I, Hirvonen J, Tuominen L, Lumme V, Vasar V, Shlik J, Nutt DJ, Helin S, Någren K, Tiihonen J, Hietala J. Gender differences in brain serotonin transporter availability in panic disorder. J Psychopharmacol. 2011; 25(7): 952-959.
Schain M, Tóth M, Cselényi Z, Stenkrona P, Halldin C, Farde L, Varrone A. Quantification of serotonin transporter availability with [11C]MADAM - a comparison between the ECAT HRRT and HR systems. Neuroimage 2012; 60(1): 800-807.
Schain M, Tóth M, Cselényi Z, Arakawa R, Halldin C, Farde L, Varrone A. Improved mapping and quantification of serotonin transporter availability in the human brainstem with the HRRT. Eur J Nucl Med Mol Imaging 2013; 40(2): 228-237.
Stenkrona P, Halldin C, Lundberg J. 5-HTT and 5-HT1A receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects. Eur Neuropsychopharmacol. 2013; 23(10): 1190-1198.
Takano A, Halldin C, Farde L. SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study. Psychopharmacology (Berl). 2013; 226(1): 147-153.
Tuominen L, Salo J, Hirvonen J, Någren K, Laine P, Melartin T, Isometsä E, Viikari J, Cloninger CR, Raitakari O, Hietala J, Keltikangas-Järvinen L. Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort. Psychol Med. 2013; 43(4): 881-894.
Tuominen L, Nummenmaa L, Keltikangas-Järvinen L, Raitakari O, Hietala J. Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems. Hum Brain Mapp. 2014; 35(5): 1875-1884.
Created at: 2009-03-22
Updated at: 2014-06-25
Written by: Vesa Oikonen