Lipophilicity coefficients of potential tumor imaging agents, positron‐labeled O⁶‐benzylguanine derivatives

Abstract

Novel radiolabeled O(6)-benzylguanine (O(6)-BG) derivatives, 6-O-[(11)C]-[(methoxymethyl)benzyl]guanines ([(11)C]p-O(6)-MMBG, 1a; [(11)C]m-O(6)-MMBG, 1b; [(11)C]o-O(6)-MMBG, 1c), 2-amino-6-O-[(11)C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([(11)C]p-O(6)-AMMP, 2a; [(11)C]m-O(6)-AMMP, 2b; [(11)C]o-O(6)-AMMP, 2c), 2-amino-6-O-[(11)C]-[(methoxymethyl)benzyloxy]-9-benzyl purines ([(11)C]p-O(6)-AMBP, 3a; [(11)C]m-O(6)-AMBP, 3b; [(11)C]o-O(6)-AMBP, 3c), 2-amino-6-O-benzyloxy-9-[(11)C]-[(methoxycarbonyl)methyl]purine ([(11)C]ABMMP, 4), and 2-amino-6-O-benzyloxy-9-[(11)C]-[(4'-methoxycarbonyl)benzyl]purine ([(11)C]ABMBP, 5), have been synthesized for evaluation as potential novel positron emission tomography tumor imaging agents. The ability of O(6)-BG analogs to penetrate the blood--brain barrier in brain tumor could be due, at least in part, to their lipophilicity. In this paper, we measured lipophilicity coefficients (log P) of compounds 1--5 by the C(18) HPLC method. These log P values were compared, and correlations between lipophilicity and biological activity of selected analogs were made. The results suggest the appropriate level of lipophilic character in this class of compounds as useful imaging agents appears to be in the range of 1.4--2.6.

A Laboratory-Specific Scaling Factor to Predict the In Vivo Human Clearance of Aldehyde Oxidase Substrates

“…Chemical structure of aldehyde oxidase substrate that have reported IV clearance. (Liu et al, 2005) 3 Renal clearance (L/h) 0.12 (Dolan et al, 1998;Tserng et al, 2003) 1.94 (Hutzler et al, 2012) 0 (Kaye et al, 1984) -1.65 (Micel i et al, 2005) 16. (Dalvie et et al, 2003(Dalvie et et al, ) et al, 2012(Dalvie et et al, ) al., 1984(Dalvie et et al, ) et al, 1999 al (Roy et al, 1995;Zientek et al, 2010) 860.7 (Hutzler et al, 2012) 446 (Zientek et al, 2010;Fu et al, 2013) 3.9 (Lake et al, 2002;Zientek et al, 2010) 410.3 (Obach et al, 2012) 41.2 (Dalvie et al, 2010;Zientek et al, 2010;Fu et al, 2013) Measured (this study) 10.9 1062 175 1.86 33.4 13.1…”