The simplified reference tissue model (SRTM) of Lammertsma et al. [21] is a further development of the 4 parameter reference tissue model. Introducing a new constraint, it reduces the number of fit parameters from four to three.

SRTM is based on the following assumptions:

- The distribution volume is the same for the tissue of interest and the reference tissue: K
_{1}/k_{2}=K_{1}'/k_{2}'. - The kinetics in the receptor-rich tissue of interest is such, that it is difficult to distinguish between the specific and the free/non-specific compartment; ie. the TAC can be fitted by a 1-tissue compartment model. This assumption may not be valid for all tracers. (Even in the test data, the approximation is not accurate at early time points.)

Defining R_{1}=K_{1}/K_{1}' as the ratio of tracer delivery, and the binding potential BP as k_{3}/k_{4}, the following operational equation can be derived for the measured TAC in the receptor-rich region:

The three unknowns R_{1}, k_{2}, BP, in this equation can be fitted using nonlinear regression techniques.

**Note: **In cases where the 1-tissue compartment model assumption does not apply, BP estimates from SRTM have found to be biased [43].

Implementation Notes

After switching to the **Simplified Ref Tissue Model** in PKIN a suitable reference region must be selected. For convolution with the exponentials, the reference tissue TAC is resampled on a regular grid, which can be specified by the **resampling interval** parameter in PKIN.

Note that **k**_{2}', the transfer of tracer from the reference tissue back to the plasma, is also calculated as a derived parameter. This value can be used in the SRTM2 and the MRTM2 reference methods.

**Note:** The reference methods MRTM2 and SRTM2 require k_{2}'_{ }as an input parameter. The k_{2}' resulting from the SRTM method above is a suitable estimate. Therefore, when switching in PKIN from the SRTM model to the SRTM2 or MRTM2, k_{2}'_{ }is automatically copied from SRTM, as long as **Model conversion** in the **Configuration **menu is enabled.

Abstract [21]

"The reference tissue model allows for quantification of receptor kinetics without measuring the arterial input function, thus avoiding arterial cannulation and time-consuming metabolite measurements. The model contains four parameters, of which the binding potential (BP) is the parameter of interest. Although BP is robust, convergence rates are slow and the other parameters can have large standard errors. To overcome this problem, a simplified reference tissue containing only three parameters was developed. This new three-parameter model was compared with the previous four-parameter model using a variety of PET studies: [11C]SCH 23390 (D1 receptor) and [11C]raclopride (D2 receptor) in humans, and [11C]SCH 23390, [11C]raclopride and [11C]RTI-121 (dopamine transporter) in rats. The BP values obtained from both models were essentially the same for all cases. In addition, the three-parameter model was insensitive to starting values, produced stable results for the other parameters (small standard errors), and converged rapidly. In conclusion, for the ligands tested the three-parameter model is a better choice, combining increased convergence rate with increased stability."