General Approaches Using Radiolabeled Tracers in Drug Discovery

Most studies used in drug development apply the tracer principle to specific examples involving recep-tor/ transporter binding drugs. Receptor binding studies generally use one of the following methods:

1. To determine the interaction of the drug with a desired binding site (e.g., receptor or enzyme):

a. Radiolabelled the potential drug in such a way as to not disturb the biochemical parameter to be measured.

b. Use a radioligand with the desired properties and study potential drug candidate binding by competition. Usually co-injection is used, but pre-or post-injection may be required depending on the relative pharmacokinetics. Measure neurotrans-mitter concentration changes with reversible receptor radioligand indirectly after administering the potential drug, whose putative mode of action is through neurotransmitter release. One example of this is the use of [11C]-raclopride, a dopamine receptor antagonist, to indirectly measure increases in the neurotransmitter dopamine as a function of the pharmacologic action of an amphetamine-like potential drug candidate [13], or,

2. Measure enzyme inhibition indirectly by measuring neurotransmitter concentration. An example is the measurement of the effect of cholinesterase inhibitors on the increase in acetylcholine concentration. This increase is measured indirectly by using a radiolabelled muscarinic receptor agonist that is bound reversibly [14].

Radiolabelling the potential drug was not the method of choice in this symposium and other such symposia. The approaches described in 1b and 2 above offer the advantage of quick answers because the radiotracer is already characterized, a clear advantage given the cost of delaying new drug development [15]. In this era of increased interest in surrogate or mechanistic markers to accelerate the drug development process, nuclear medicine imaging is an important technique and an unique approach when low-density binding sites are the drug targets. The one negative implication of the approach outlined in 1b or 2 is that the drug being developed is in an area that is well enough characterized such that radioligands have already been developed for immediate use. In general, new targets are the goal of pharmaceutical discovery, which implies that a new radioligand will have to be developed, which could slow the drug development in this new therapeutic area.

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