Receptor Binding Radiotracer

The use of radiotracers in the analysis of the immuno-logical and molecular properties of the sentinel lymph node in cancer is a new area that is attracting attention in both diagnosis and therapy. This effort promises to yield diagnostic approaches that will result in rapid

The muscarinic acetylcholine receptor (mAChR) was one of the earliest receptors studied with in vivo techniques. As early as 1973, Farrow and O'Brien [33] described the use of [3H]-atropine to define the mAChR.

With the development of higher affinity and higher specific activity compounds such as [3H]-QNB, receptor distribution was mapped in isolated tissue [34,35]. The first ligand to map mAChR in humans in vivo was the radioiodinated form of QNB, 3-R-quinuclidinyl 4-S-iodobenzilate (RS IQNB) [36]. The use of receptor-binding radiotracers for external brain imaging differs from their use in vitro. For a radiotracer to be useful in vivo, its distribution must be driven by the local receptor concentration rather than by local blood flow or membrane transport properties, so that the images obtained primarily reflect receptor binding. A comprehensive kinetic analysis of RS IQNB in rats was performed by Sawada et al. [37], it showed that the uptake in cerebrum is essentially irreversible during the first 360 minutes after intravenous administration and that the rate of RS IQNB tissue uptake depends on transport across the blood-brain barrier (BBB) and the rate of binding to the receptor. However, after about 24 hours the data showed a sensitivity to receptor concentration. Clinical studies with RS IQNB indicate that it is responsive to changes in receptor concentration at 18-24 hours post-injection [38,39]. However, it does not demonstrate significant muscarinic subtype selectivity.

Our early work on muscarinic ligands was based on antagonist analogs of quinuclidinyl benzilate (QNB) but, more recently, we have used analogs of 3-alkyl-(1,2,5-thiadiazol-4-yl)-tetrahydro-1-methylpyridine (TZTP). We have investigated both antagonists and agonists, because the former usually have higher affinity and therefore may give more image contrast, while the latter may provide more biologically relevant information by being sensitive to the affinity state of the receptor. The primary goal is the development of tracers with selectivity for the M2 site. In general, M2 subtype specificity cannot be demonstrated by the usual proofs of regional distribution of receptor and the pharmacologic profile. Unlike other receptor systems (e.g., D2), the distribution of the M2 receptor population is highly uniform, so the radioactivity distribution does not provide compelling evidence. In addition, subtype-selective in vivo blocking studies are problematic because of the lack of other high-affinity M2 ligands that cross the BBB. Furthermore, the use of antagonists to block agonist ligands has not been demonstrated. Therefore, we were able to block [18F]-FP-TZTP only with compounds of the same chemical class. Our work on muscarinic ligands described below is based on our hypothesis that subtype selective ligands will be more effective in studying biochemistry in vivo than the more nonselective radiotracers used to date.

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