Binding potential

Bmax is the total density (concentration) of receptors in a sample of tissue. To refer to the concentration of available (free) receptors, terms Bavail or B'max can be used.

KD is the (radioligand) equilibrium dissociation constant. Affinity of ligand binding is the inverse of KD.

Binding potential (BP) is the ratio of Bmax to KD, as defined by Mintun et al (1984).

BP can be estimated from a single PET study, while estimation of Bmax and KD requires at least two PET studies.

In vitro at tracer doses, BP equals the ratio of specifically bound ligand to its free concentration.

In vivo not all of receptors are available for the radioligand to bind because of occupancy by endogenous ligands (or drugs in receptor occupancy studies). Therefore, in in vivo imaging the term Bavail is often used instead of Bmax. Assuming that radioligand is not actively transported into tissue or out from tissue, so that at equilibrium the free concentration in plasma (CFP) equals the free concentration in tissue (CFT),

In terms of volumes of distribution,

, where VT and VND could be estimated from region-of-interest and reference region, respectively, for example with Logan plot. Calculation of BPF requires plasma sampling and measurement of plasma protein binding (plasma free fraction fP).

Usually, the determination of fP is omitted because it is prone to errors and would merely add more variability to results. Then, the specific binding in tissue is compared to not free but total plasma concentration:

Specific binding is defined as the radioligand binding to the target receptor, not including the binding to other macromolecular components or radioligand that is not bound at all (free) in the tissue sample.

Nonspecific (NS) binding is the radioligand binding to other than the target molecule.

Non-displaceable (ND) radioligand uptake is the sum of nonspecific and free (F) radioligand concentrations in tissue. This uptake can not be abolished by adding large amounts of non-labelled ("cold") ligand that binds to the same receptor.

If specific uptake is not compared to plasma concentrations but to non-displaceable tissue uptake, we can determine BPND:

, where the term VT / VND is often referred to as distribution volume ratio (DVR). BPND is dependent on the fraction of non-displaceable binding in the tissue, fND:

DVR can be estimated without plasma sampling using for example (simplified) reference tissue compartment model or Logan plot with reference tissue input. However, BPND could also be calculated from distribution volumes that are estimated using plasma sampling.

fND and fP

Tissue free fraction (fND, or previously also marked as f2) is the fraction of radioligand or drug that is freely dissolved in tissue water. It is expressed relative to the non-displaceable tissue concentration (CND):

In a two-tissue compartment model fND affects both k2 and k3.

Free fraction of radioligand or drug in plasma (fP, or previously also marked as f1) is the fraction of the ligand that is not bound to plasma proteins at equilibrium. Thus, the concentration of radioligand freely diffusible in plasma water and available for transport into tissue can be calculated as

Blood flow does not affect binding potential

Changes in receptor availability are often physiologically linked to changes in tissue blood flow (perfusion). This does not mean that the estimated binding potential, VT, or DVR is biased, since changes in perfusion are reflected in the plasma-to-tissue influx rate constant K1 and efflux rate constant k2. Binding potential is not dependent on either K1 or k2, and VT is dependent on the ratio of K1 and k2, from which the effect of blood flow is cancelled out.

The fact that radioligand receptor binding can be assessed independently of altered delivery has been validated in several PET studies, for example for [11C]FMZ (Holthoff et al., 1991), [11C]raclopride and [18F]fallypride (Sander et al., 2019), and [11C]UCB-J (Smart et al., 2021).


See also:


References:

Gjedde A, Bauer WR, Wong DF: Neurokinetics: The Dynamics of Neurobiology in Vivo. Springer, 2011. doi: 10.1007/978-1-4419-7409-9.

Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN. A graphical method to compare the in vivo binding potential of PET radioligands in the absence of a reference region: application to [11C]PBR28 and [18F]PBR111 for TSPO imaging. J Cereb Blood Flow Metab. 2014; 34: 1162-1168. doi: 10.1038/jcbfm.2014.65.

Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007; 27(9): 1533-1539. doi: 10.1038/sj.jcbfm.9600493.

Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol. 1984; 15: 217-227. doi: 10.1002/ana.410150302.

Morris ED, Chefer SI, London ED: (1998) Limitations of binding potential as a measure of receptor function: a two-point correction for the effect of mass. In: Quantitative Functional Brain Imaging with Positron Emission Tomography (Eds: Carson et al.). Academic Press, San Diego, pp 407-413.

Slifstein M, Laruelle M. Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl. Med. Biol. 2001; 28: 595-608. doi: 10.1016/s0969-8051(01)00214-1.



Tags: , , , , , ,

Updated at: 2020-12-11
Created at: 2007-09-01
Written by: Vesa Oikonen