Fitting the fractions of unchanged tracer in plasma
The chromatographic methods used in the metabolite analysis are slow, and hampered by the fast decay of radioactivity, especially with C-11 labelled tracers. The fractions can often be determined only from sparse samples with increased uncertainty with time. Fitting of an empirical mathematical function to the fraction curves reduces variation and enables extrapolation, and may thus be required to achieve an acceptable metabolite correction.
Parent fraction fitting could also enable simple correction of ex vivo tracer metabolism during blood sample preparation before the chromatographic methods (Oikonen, 2014), but this approach must be validated for each tracer and metabolite analysis protocol.
Compartmental models can be used to model the appearance of metabolites in the plasma or blood (Huang et al., 1991). A variety of mathematical functions can be applied to different tracers (Tonietto et al., 2016). For most tracers fitting the sigmoidal “Hill type” or power functions can be recommended: in practise, the curves of unchanged tracer fractions often do show a sigmoid shape, and could not be described by declining exponential functions. This may be caused by slow injection of tracer, or a redistribution phase of tracer from an initial deposition to a highly perfused tissue, mainly lungs, which may include specific binding to for instance serotonin transporters (Suhara et al., 1998). Metabolites should not appear in blood samples before the circulation time (normally 1 min) is passed, unless tracer is metabolised in the lungs or by enzymes in blood (Hinz et al., 2007). Parent tracer fraction at t=0 may be <1.0 also if the administered radioligand is not 100% pure, which is common in preclinical animal studies.
Sigmoidal fraction curve can also be fitted using a function suggested by Sorger et al (2007):
In this function f0 is the initial fraction, which can be markedly lower than one in early preclinical studies with poor radiochemical purity.
Declining exponential functions may be preferred in some cases, especially in small animal studies where circulation is fast and the initial ‘shoulder’ cannot be observed. For example, this function
Simple two-exponential function with background was used in [18F]fallypride radiometabolite analysis study (Peyronneau et al., 2013):
Two-exponential function could be presented so that the relative weights of the exponentials are easily seen:
In brain receptor studies where a reference region, for example cerebellum, is available, the terminal rate of radiotracer washout from the reference region and the smallest elimination rate of constant of the total plasma curve can be used to constrain the second exponential of the two-exponential function for the parent fraction (Abi-Dargham et al., 1999).
Two-exponential function can even be used to fit sigmoidal data, as proposed by Blomqvist et al. (1990):
, where the parameters are interchangeable but b1 ≠ b2.
One-phase exponential (monoexponential) function
, where A0 and Ai represent the level at time 0 and at infinity, respectively, and k represents the decay constant, may also be useful in fitting parent tracer fractions, and plasma-to-blood ratio data with certain tracers.
Naganawa et al (2014a, 2014b) fitted a function based on cumulative (regularized) gamma distribution to plasma parent fraction data from [11C]GR103545 and [11C]LY2795050 (tracers for κ opioid receptors) PET studies, but the function would be applicable to most PET tracers. The function has four parameters (a-d), where a and b define the overall and end level of the parent fraction, and c and d affect the shape of the gamma distribution function.
Standard gamma distribution function has two parameters x and α, gammadist(x, α). The proposed function for the plasma parent tracer fractions as a function of time, t, is:
Tonietto et al (2015) validated a method where the bolus injection is modelled as a boxcar function, convoluted with power, Hill, or exponential function.
For certain tracers, the fraction of non-metabolized parent tracer in plasma is not approaching 1.0 at the injection time, but may even be increasing during the first few minutes of the study. This has been shown for a tracer ([11C]DASB) binding to 5-HT transporters, possibly caused by transient trapping of parent tracer in the lungs, while the radioactive metabolite has no affinity for the 5-HT transporter (Parsey et al., 2006). A power-function-damped 2-exponential function
was shown to fit the metabolite data better and improve test-retest reproducibility (Parsey et al., 2006).
Another extension to power function was used by Hinz et al. (2007).
Fraction data are usually either not weighted, or weighted by 1 / sampling frequency to prevent overfitting the initial part with more frequent sampling. However, fractions could also be weighted based on count statistics (Tsujikawa et al., 2014).
Function parameters are saved into specific fit file format, which are ASCII text files.
If the fractions of unchanged tracer in plasma or blood are very variable or measurements are missing for a few subjects, then a population based method should be considered. It may be useful to constrain one or more function parameters to population mean to reduce the number of blood samples for metabolite analysis.
- Metabolite correction
- Fractions of unchanged tracer in plasma
- Hill function in plasma metabolite correction
- Power function in metabolite correction
- Compartmental models for plasma metabolite correction
- Fitting PET input curves
- Processing input data
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Updated at: 2019-01-15
Created at: 2007-07-18
Written by: Vesa Oikonen