Molecular modeling of hexakis(areneisonitrile)technetium(I), tricarbonyl h 5 cyclopentadienyl technetium and technetium(V)-oxo complexes: MM3 parameter development and prediction of biological properties Peter Wolohan, David E. Reichert * Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States Received 1 December 2005; received in revised form 26 April 2006; accepted 27 April 2006 Available online 16 May 2006 Abstract Genetic algorithms (GA) were used to develop specific technetium metal–ligand force field parameters for the MM3 force field. These parameters were developed using automated procedures within the program FFGenerAtor from a combination of crystallographic structures and ab initio calculations. These new parameters produced results in good agreement with experiment when tested against a blind validation set. To illustrate the utility of these new force field parameters, quantitative structure–activity relationship (QSAR) models were developed to predict the P-glycoprotein uptake (log 10 VI) of a series of hexakis(areneisonitrile)technetium(I) complexes and to predict their biodistribution. The log 10 VI QSAR model, built using a training set of 16 Tc(I) isonitrile complexes, exhibited a correlation between the experimental log 10 VI and 5 simple descriptors as follows: r 2 = 0.94, q 2 = 0.93. When applied to an external test set of six Tc(I) isonitrile complexes, the QSAR preformed with great accuracy q 2 = 0.78 based on a leave-one-out cross-validation analysis. Further QSAR models were developed to predict the biodistribution of the same set of Tc(I) isonitrile complexes; a QSAR model to predict hepatic uptake exhibited a correlation between the experimental log 10 (Blood/ Liver) with six simple descriptors as follows: r 2 = 0.97, q 2 = 0.96. A QSAR model to predict renal uptake exhibited a correlation between the experimental log 10 (Blood/Kidney) and six simple descriptors as follows: r 2 = 0.85, q 2 = 0.82. When applied to the external test set the QSAR models preformed with great accuracy, q 2 = 0.78 and 0.56, respectively. # 2006 Elsevier Inc. All rights reserved. Keywords: Technetium; MM3 parameters; QSAR; P-glycoprotein 1. Introduction The radionuclide 99m Tc is the most widely utilized radionuclide for diagnostic imaging in nuclear medicine. This is a result of several factors, its high specific activity and availability though the 99 Mo generator, its convenient 6 h half- life, and its emission of a 140 keV g -ray with 89% abundance which is ideal for imaging with the standard gamma cameras found in almost all hospitals. The Federal Drug Administration (FDA) has approved numerous technetium radiopharmaceu- ticals for use as diagnostic imaging agents [1–3]. 99m Tc-sestamibi (Fig. 1) is approved for myocardial perfusion imaging and breast cancer [4], and it is also used for the functional detection in vivo of human multidrug resistance (MDR1) P-glycoprotein (Pgp) expression in human tissue [5,6]. [ 99m Tc] TRODAT-1 (Fig. 1) based on a diaminodithiol radionuclide chelate and a tropane precursor is a primary ligand used to image the dopamine transporter [7]. The dopamine transporter (DAT), which is found in the presynaptic neurons concentrated in the striatum of the brain, has been found to play an important role in Parkinson’s disease, addiction and schizophrenia [8]. Tc(I)-tetrakis(tert-butylisoni- trile) radiometal complexes containing a bidentate aromatic dye moiety such as Congo Red have been used to image Alzheimer’s disease as a result of their binding to b1–40 amyloid fibrils [9]. The diaminodithiol Tc(V)-oxo scaffold together with tricarbonyl technetium steroid based derivatives (Fig. 1) have been used to develop imaging agents for the nuclear hormone www.elsevier.com/locate/JMGM Journal of Molecular Graphics and Modelling 25 (2007) 616–632 * Corresponding author at: Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Campus Box 8225, St. Louis, MO 63110, United States. Tel.: +1 314 362 8461; fax: +1 314 362 9940. E-mail address: reichertd@wustl.edu (D.E. Reichert). 1093-3263/$ – see front matter # 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2006.04.007