Population-based input function (PBIF)

Quantitative PET studies require that input function (IF), representing cumulative availability of the radiopharmaceutical in arterial plasma, is available. Measurement of arterial input function (AIF) is invasive, and can be difficult, especially in small animals (Laforest et al., 2005), without disturbing the physiologic status. One approach is to extract image-derived input function (IDIF) from a large blood vessel or left cardiac ventricle in dynamic image, but also it is associated with several problems that must be solved and methods well validated before using in clinical studies (Zanotti-Fregonara et al., 2011; Christensen et al., 2014). Model-derived input methods do not require that pixels representing blood curve were to be found in the PET image, but rely on assumption that the input function is common to all tissue regions in the image, and can be solved from the data. The outcome does not need any further corrections, since it already represents metabolite-corrected arterial plasma, except that it still needs to be scaled to the correct level using reference region, blood sample(s), or injected dose, BMI or BSA; this requirement applies also to image-derived and model-based input function (Zanderigo et al., 2015; Bartlett et al., 2018).

Population-based input function (PBIF, also called standard arterial input function, SAIF) is based on the individual scaling of a radiopharmaceutical- and population-specific input curve (Zanotti-Fregonara et al., 2013; Rissanen et al., 2015). The scaling can be based on injected dose and subject mass, venous blood sample, or reference tissue in the PET image. Standardized radioligand administration method, preferably with infusion pump, will produce the best results. PBIF is usually represented by a mathematical function. For PBIF methods to work, injection protocol must be the same in all PET studies. Dose extravasation is not acceptable, because that will change the shape and/or level of arterial blood time-activity curve (BTAC).

PBIF can also be applied in arterial sampling protocol with only few samples covering the scan length. Contractor et al. (2012) applied this method for [18F]fluorothymidine PET studies.


Arterial or arterialized venous blood sample(s) have been used to scale PBIF (Takikawa et al., 1993; Eberl et al., 1997; Olshen & O'Sullivan, 1997; Graham et al., 2000; Sundaram et al., 2004; Brock et al., 2005; Vriens et al., 2009). Population approach and scaling can be combined with fitting a function to few late samples, fixing some of the function parameters to population mean (Phillips et al., 1995). Injected dose and and patient weight, lean body weight, or BSA can also be used to scale PBIF (Hunter et al., 1996; Tsuchida et al., 1999; Shiozaki et al., 2000). Cerebellum could be used as a reference tissue to scale PBIF in a study of healthy human volunteers, when autoradiographic method was used to compute parametric images (Bentourkia, 2006). Christensen et al. (2014) compared several published methods for deriving noninvasive input function in PET studies of the thigh region.

In rat studies PBIF method, based on either injected dose and animal weigh or a single blood sample, performed equally well as arterial sampling (Meyer et al., 2006; Hori et al., 2015). In contrast, Meyer et al. (2017) noticed high variability in mice studies, caused by different shapes of arterial BTACs. In mouse studies PET radiopharmaceutical is usually injected into the tail vein, which often leads to extravasation, changing the shape and/or level of the input function.


Standard arterial input function can be used to improve the quantitation of regional blood flow changes in brain activation studies, which otherwise often were conducted without arterial sampling (Sadato et al., 1993; Treyer et al., 2003). Clinically relevant perfusion images for oncological PET studies can be computed using dose and patient mass or BSA scaled PBIF (Komar et al., 2012).


Venous blood samples have been used to scale PBIF (Cook et al., 1999 and 2000) in [18F]fluoride PET studies.

TSPO radiopharmaceuticals

PBIF method for [18F]FEPPA requires one arterial plasma sample with metabolite correction, and method still increases the variability, requiring increase in sample size (Mabrouk et al., 2017). In non-human primate studies with [11C]PBR28 PBIF scaling with a single blood sample performs better than pseudo-reference region approaches (Aceves-Serrano et al., 2022).


Population-derived input function, scaled using venous blood samples, has been validated for L-[1-11C]leucine PET studies in healthy human subjects (Tomasi et al., 2018).

See also:


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Christensen AN, Reichkendler MH, Larsen R, Auerbach P, Højgaard L, Nielsen HB, Ploug T, Stallknecht B, Holm S. Calibrated image-derived input functions for the determination of the metabolic uptake rate of glucose with [18F]-FDG. Nucl Med Commun. 2014; 35: 353-361. doi: 10.1097/MNM.0000000000000063.

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Eberl S, Anayat AR, Fulton RR, Hooper PK, Fulham MJ. Evaluation of two population-based input functions for quantitative neurological FDG PET studies. Eur J Nucl Med. 1997; 24(3): 299-304. doi: 10.1007/BF01728767.

Hori Y, Ihara N, Teramoto N, Kunimi M, Honda M, Kato K, Hanakawa T. Noninvasive quantification of cerebral metabolic rate for glucose using 18F-FDG PET and standard input function. J Cerebr Blood Flow Metab. 2015; 35: 1664-1670. doi: 10.1038/jcbfm.2015.104.

Komar G, Oikonen V, Sipilä H, Seppänen M, Minn H. Noninvasive parametric blood flow imaging of head and neck tumours using [15O]H2O and PET/CT. Nucl Med commun. 2012; 33(11): 1169-1178. doi: 10.1097/MNM.0b013e3283579e6e.

Mabrouk R, Strafella AP, Knezevic D, Ghadery C, Mizrahi R, Gharehgazlou A, Koshimori Y, Houle S, Rusjan P. Feasibility study of TSPO quantification with [18F]FEPPA using population-based input function. PLoS One 2017; 12(5):e0177785. doi: 10.1371/journal.pone.0177785.

Meyer PT, Circiumaru V, Cardi CA, Thomas DH, Bal H, Acton PD. Simplified quantification of small animal [18F]FDG PET studies using a standard arterial input function. Eur J Nucl Med Mol Imaging 2006; 33(8): 948-954. doi: 10.1007/s00259-006-0121-7.

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Zanderigo F, Ogden RT, Parsey RV. Noninvasive blood-free full quantification of positron emission tomography radioligand binding. J Cereb Blood Flow Metab. 2015; 35: 148-156. doi: 10.1038/jcbfm.2014.191.

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Zanotti-Fregonara P, Hirvonen J, Lyoo CH, Zoghbi SS, Rallis-Frutos D, Huestis MA, Morse C, Pike VW, Innis RB. Population-based input function modeling for [18F]FMPEP-d2, an inverse agonist radioligand for cannabinoid CB1 receptors: validation in clinical studies. PLoS One. 2013; 8(4): e60231. doi: 10.1371/journal.pone.0060231.

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Updated at: 2022-12-13
Created at: 2017-12-16
Written by: Vesa Oikonen