Cortical D2/3R availability with [11C]FLB457

[11C]FLB457 (Halldin et al., 1995) is a high affinity dopamine D2/3 receptor PET radioligand, which can be used to assess the density of cortical (extrastriatal) D2/3Rs (Olsson et al., 2004; Sudo et al., 2001; Suhara et al., 1999; Vilkman et al., 2000). Striatal D2/3R density is too high to be reliably assessed with [11C]FLB457; instead, striatal density is measured with [11C]raclopride that does not provide sufficient signal-to-noise ratio to quantify the relatively low density of dopamine receptors in extrastriatal areas. Even for [11C]FLB457 the signal-to-noise ratio is low in cortical regions, making analysis challenging but not impossible.

there has been some controversy on whether [11C]FLB457 is suitable for assessing cortical dopamine (DA) function, that is, to measure acute changes in synaptic DA concentration. In some studies this has not been successful (Okauchi et al., 2001; Aalto et al., 2009; Frankle et al., 2010), but nevertheless this application of [11C]FLB457 PET has provided meaningful results in several studies (Montgomery et al., 2007; Narendran et al., 2009, 2013, and 2014; Ko et al., 2009; Sandiego et al., 2015 Slifstein et al., 2015). For thalamus [11C]FLB457 works well.

Data analysis

Arterial input function

Arterial blood needs to be sampled through the whole scan time, usually 90 min. Blood curve has been collected using ABSS for the initial period. Metabolite correction is necessary, and parent fraction data can be fitted with an inverted gamma function (Sandiego et al., 2015) or Hill-type function (Frankle et al., 2010).

Compartmental model

2-tissue compartment model (2TCM) has been used to analyse cortical data. Slifstein et al (2015) incorporated a set of shared parameter estimates (K1/k2 and k4) across regions to improve reliability of fitting to address the issue of low signal-to-noise ratio. K1 and k3 were fitted in each region. All regions were weighted equally in the the fitting. The same procedure was applied separate to cortical and subcortical regions, because in subcortical regions k4 may be different due to higher [11C]FLB457 binding. Binding potential (BPND) was estimated directly from the ratio k3/k4. Distribution volume was calculated as VT = (K1/k2) × (1 + BPND). Simulations showed that fitting baseline and post-amphetamine challenge data simultaneously, with common K1/k2 and k4, performed better than fitting them separately; with this method it was possible to show that capacity for amphetamine induced Dopamine release is reduced in dorsolater prefrontal cortex of patients with schizophrenia, and that more widespread deficit extending to many cortical and extrastriatal regions including the midbrain is probable (Slifstein et al., 2015). Without shared parameter estimation the reproducibility is poor (Vilkman et al., 2000).

Reference region

Cerebellum has very low density of D2Rs (Suhara et al., 1999), but it is still not optimal reference region for fully quantitative analysis of cortical regions where D2 receptor density is low, too, and results may be susceptible to changes in blood flow (Asselin et al., 2007). Cerebellum has been successfully used as a reference region in group comparison studies.

When metabolite-corrected plasma curve is measured, 2TCM derived VTs from cortical regions and cerebellum have been used to calculate distribution volume ratio and further BPND (Vilkman et al., 2000; Sandiego et al., 2015). This method has for example revealed the effect of C957T polymorphism of the D2R gene on extrastriatal [11C]FLB457 binding (Hirvonen et al., 2009).

With metabolite-corrected plasma input function, VTs can also be estimated using Logan plot. BPND estimated this way has good reproducibility (Vilkman et al., 2000).

SRTM with cerebellum as reference region underestimates BPND, compared to 2TCM-derived BPND; yet, amphetamine-induced DA release could be observed in extrastriatal regions only using SRTM (Sandiego et al., 2015). STRM has been used in drug occupancy studies (Arakawa et al., 2010), and it has successfully shown for example age-related extrastriatal D2/3R loss (Kaasinen et al., 2000), link between D2/3Rs and executive functioning (Lumme et al., 2007), μ-agonist alfentanil-induced changes (Hagelberg et al., 2004), the effects of GABAAR targeting lorazepam on extrastriatal D2/3R availability (Vilkman et al., 2010), and psychotherapy-induced changes in social anxiety disorder (Cervenka et al., 2012).

Logan plot with cerebellum as reference region provides cortical BPND with similar accuracy than arterial plasma based methods (Vilkman et al., 2000). It has been used to calculate regional thalamic BPND (Plavén-Sigray et al., 2022).

Non-intentional changes in cerebellar binding could be assessed if arterial plasma input function is available. VT could then be estimated with Logan plot (Vilkman et al., 2000) or compartmental model fitting, for example with multilinear solution of 2TCM (Hagelberg et al., 2004).


See also:


Literature

Asselin MC, Montgomery AJ, Grasby PM, Hume SP. Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region. J Cereb Blood Flow Metab. 2007; 27(2): 378-392. doi: 10.1038/sj.jcbfm.9600340.

Cselényi Z, Olsson H, Halldin C, Gulyás B, Farde L. A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635. Neuroimage 2006; 32: 1690-1708. doi: 10.1016/j.neuroimage.2006.02.053.

Farde L, Suhara T, Nyberg S, Karlsson P, Nakashima Y, Hietala J, Halldin C. A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients. Psychopharmacology (Berl). 1997; 133(4): 396-404. doi: 10.1007/s002130050420.

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Hirvonen MM, Lumme V, Hirvonen J, Pesonen U, Någren K, Vahlberg T, Scheinin H, Hietala J. C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(4): 630-636. doi: 10.1016/j.pnpbp.2009.02.021.

Ikoma Y, Ito H, Arakawa R, Okumura M, Seki C, Shidahara M, Takahashi H, Kimura Y, Kanno I, Suhara T. Error analysis for PET measurement of dopamine D2 receptor occupancy by antipsychotics with [11C]raclopride and [11C]FLB 457. Neuroimage 2008; 42(4): 1285-1294. doi: 10.1016/j.neuroimage.2008.05.056.

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Narendran R, Mason NS, May MA, Chen CM, Kendro S, Ridler K, Rabiner EA, Laruelle M, Mathis CA, Frankle WG. Positron emission tomography imaging of dopamine D2/3 receptors in the human cortex with [11C]FLB 457: reproducibility studies. Synapse 2011; 65(1): 35-40. doi: 10.1002/syn.20813.

Narendran R, Mason NS, Chen CM, Himes M, Keating P, May MA, Rabiner EA, Laruelle M, Mathis CA, Frankle WG. Evaluation of dopamine D2/3 specific binding in the cerebellum for the positron emission tomography radiotracer [11C]FLB 457: implications for measuring cortical dopamine release. Synapse 2011; 65(10): 991-997. doi: 10.1002/syn.20926.

Okubo Y, Olsson H, Ito H, Lofti M, Suhara T, Halldin C, Farde L. PET mapping of extrastriatal D2-like dopamine receptors in the human brain using an anatomic standardization technique and [11C]FLB 457. Neuroimage 1999; 10(6): 666-674. doi: 10.1006/nimg.1999.0502.

Olsson H, Halldin C, Swahn CG, Farde L. Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab. 1999; 19(10): 1164-1173. doi: 10.1097/00004647-199910000-00013.

Olsson H, Farde L. Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy - a simulation study based on experimental data. Neuroimage 2001; 14(4): 936-945. doi: 10.1006/nimg.2001.0879.

Vilkman H, Kajander J, Någren K, Oikonen V, Syvälahti E, Hietala J. Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457 - a test-retest analysis. Eur J Nucl Med. 2000; 27(11): 1666-1673. doi: 10.1007/s002590000342.



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Updated at: 2023-01-21
Created at: 2007-12-03
Written by: Vesa Oikonen