Lipophilicity and pK_a measurements of technetium and rhenium complexes as potential radiopharmaceuticals by using RP-HPLC

^99mTc is the most widely used radionuclide for nuclear medicine diagnostics. Efforts are made to design this unphysiological element for targeting specifically organs and cells. In this respect, lipophilic properties are of importance. We studied lipophilicity on a series of "3+1" mixed ligand oxoTc and -Re complexes with an [S-(CH₂)₂-E-(CH₂)₂-S] chelate unit [E = O, S, N-Me, N-Et] and a thiol ligand with various residues [alkyl, aryl; (CH₂)₂-NMe₂, -NEt₂,-NBu₂, -piperidinyl, -morpholinyl].
The lipophilicity/pH profiles were determined by RP-HPLC. A Perkin-Elmer HPLC Model 1022 equipped with a UV/VIS detector (254 nm) and a PRP-1 column (Hamilton, 250 x 4.1 mm, 10mm) was employed [mobile phase: isocratic eluent acetonitrile / buffer (volume ratio 3:1; pH range: 1.5 - 11); flow rate: 1.5 ml/min].
The lipophilicity determination is based on the linear relationship between the chromato-graphic retention (log k') and log D/P and results in D_HPLC/P_HPLC values. Aniline, benzene, and brombenzene were used as internal standards. The pK_a values were estimated from the turning point of sigmoidal curves and were corrected by using a calibration curve of amine standards since the measurements are performed in organic/aqueous solutions.
For amine group containing complexes (R²), that are used as models of neuroreceptor affine tracers, the influence of lipophilicity and/or pK_a on brain uptake was studied. High brain uptake relates with low pK_a, so that the highest uptake was found for morpholino-bearing complexes (0.9-2.0 % injected dose per rat brain, <5 min p.i.; pK_a 7.1-7.6). The log PHPLC values for Tc complexes are higher than for the corresponding Re complexes.