Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

Abstract

The development of reversibly binding radioligands for imaging brain proteins in vivo, such as enzymes, neurotransmitter transporters, receptors and ion channels, with positron emission tomography (PET) is keenly sought for biomedical studies of neuropsychiatric disorders and for drug discovery and development, but is recognized as being highly challenging at the medicinal chemistry level. This article aims to compile and discuss the main considerations to be taken into account by chemists embarking on programs of radioligand development for PET imaging of brain protein targets.

Translocator protein ligands based on N -methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development

“…Previously, we achieved an increase in LipE by introducing a nitrogen atom at either the 2’ position of the pendant phenyl group or the 8 position of the quinolinyl scaffold (Chart 2) [26]. We presumed that by having nitrogen atoms at both positions in the same ligand that we might significantly improve LipE, and, indeed, this turned out to be the case in ligand 20 (Table 1).…”

“…These modifications were aimed at exploring, i) variation of substituents on the amide nitrogen, ii) introduction of nitrogen into the quinolin-4-yl group or pendant aryl ring, iii) replacement of the pendant aryl ring with methoxy, 2-pyrimidinyl or N -pyrrolidinyl, iv) the effect of cyclization to eliminate amide bond rotation, and v) contraction of the bicyclic quinolinyl nucleus. Generally, PET radioligands are required to have high affinity with K D in the low nM range, and moderate lipophilicity with measured (or computed) logD in the 2–4 range [26]. Most of the changes that we made to the lead ligand scaffold were intended to retain the very high TSPO affinity ( K i = 0.07 nM for rat TSPO) seen in the previously reported example 11 (Chart 2; scaffold with Y = 2-pyridinyl, and R = Ph), as well as to decrease ligand computed lipophilicity (clog D ) from 4.73 towards the desirable range.…”

“…Successful PET radioligands for imaging specific proteins in brain are required to display a wide array of properties [26]. Among these properties are: i) high affinity and selectivity for the target protein; ii) low molecular weight; iii) intermediate polar surface area for blood-brain barrier penetration; iv) moderate lipophilicity for adequate brain entry in the absence of excessive non-specific binding; and v) amenability to labeling with a positron-emitter, either carbon-11 ( t 1/2 = 20.4 min) or fluorine-18 ( t 1/2 = 110 min).…”

In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

“…63–65 The cLog P values of compounds 8 - 11 were predicted to be 2.90, 2.90, 2.80 and 2.80, respectively (Table 1). Using liquid-liquid partition between n -octanol and water (‘shake flask method’), 66 the Log P values for 8 - 11 were determined to be 1.45 ± 0.01, 1.42 ± 0.11, 1.23 ± 0.10 and 1.17 ± 0.14, respectively ( n = 3).…”

Imaging in Central Nervous System Drug Discovery

“…The development of a successful PET biomarker is a much more challenging problem, which whilst requiring the equivalent radiochemistry expertise also includes many other complexities surrounding the compound to radiolabel. This is like a mini drug development programme in itself with the compound needing appropriate characteristics such that it readily crosses the BBB, binds with high enough affinity and selectivity to the biological target, low enough non-specific binding so background signal does not dominate and suitable kinetics so that an appropriate outcome measure can be estimated [57,58]. Since the first development of radioligands for GPCR targets in the late 80's, initial screening of compounds has focussed on identifying those with suitable lipophilicty (typically Log P 1-3) to ensure BBB penetration and nM or better affinity to yield signal at the target.…”