Crystallographic study of PET radiotracers in clinical evaluation for early diagnosis of Alzheimers1

The title compound, C24H25NO3·2CH3OH, which crystallized as a methanol disolvate, has applications as a PET radiotracer in the early diagnosis of Alzheimer’s disease. The dihedral angle between the biphenyl rings is 8.2 (2)° and the heterocyclic ring adopts a half-chair conformation with the N atom adopting a pyramidal geometry (bond-angle sum = 327.6°). The C atoms of both methoxy groups lie close to the plane of their attached ring [deviations = 0.107 (6) and 0.031 (6) Å]. In the crystal, the components are linked by O—H⋯O and O—H⋯N hydrogen bonds, generating [010] chains. C—H⋯O interactions are also observed.

Supporting information for this paper is available from the IUCr electronic archives (Reference: HB7266).

S1. Comment
The single-crystal X-ray structure solution of 4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-methyl)-biphenyl-4-ol (named MC70) radiotracer, previously pharmacologically characterized and biologically evaluated (compound 4e in Colabufo et al., 2008Colabufo et al., , 2009, has been reported. At nanomolar concentrations MC70 is a potent inhibitor of Pglycoprotein (P-gp), a membrane protein playing a protective role of the central nervous system and whose numerical and functional alteration is responsible for the onset of the Alzheimer disease. The crystallographic characterization of MC70 represents the first necessary step for a further evaluation of its pharmacological properties and to obtain, f. e. through docking techniques and homology modelling, a tridimensional interpretation of the main molecular determinants responsible for most of MC70 features such as to be an inhibitor of the P-gp. The study of this behaviour will allow the design of new ligands, more effective and selective in the monitoring the role of P-glycoprotein for the recognition and early treatment of the Alzheimer disease. In addition, up to now none of the studies on interactions of this pump with known inhibitors, report crystallographic data of P-gp inhibitors complexes. Therefore speculating the binding conformation and pose for MC70 might be an added value to a better understanding of the mechanism of action of efflux pumps involved in the Alzheimer's disease.
A view of the refined crystal structure is shown in Figure 1. The packing of the obtained crystal structure is represented in Figure 2; it is interesting observing that the network of the structure features three hydrogen bonds (Table 1): the first between the 2 molecules of methanol, the second between one methanol molecule and the phenolic residue of the molecule and the last between the other methanol molecule and the isoquinoline nucleus. In the crystal weak C-H···O hydrogen bonds also occur. In addition, the pendant biphenyl has an equatorial configuration as proved by a dihedral angle among atoms C8-N1-C7-C18 of -175°.

S3. Refinement
The hydrogen atoms of the hydroxyl groups were located by difference Fourier synthesis and freely isotropically refined. aromatic H atoms, respectively, and constrained to ride on their parent atoms. The constraint U iso (H) = kU eq (C), where k = 1.5 for methyl and k = 1.2 for aromatic and methylene H atoms, was applied. The highest residual electron density was found 1.59 Å from C16 and the deepest hole 1.04 Å from H12A.

Figure 1
The molecular structure of the MC70 compound with displacement ellipsoids drawn at the 50% probability level. Crystal packing of the MC70 compound. The light blue dashed lines show the hydrogen bonds (see Table 1 for details).

Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.