Investigating experimental vs. Predicted pK a values for PET radiotracer

The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood-brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pK values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pK values are often missing and published experimental pK values are limited especially for radiopharmaceuticals. This comparative study investigated the discrepancies between predicted and experimental pK values and their impact on CNS activity prediction scores. The pK values of 46 substances, including therapeutic drugs and PET imaging radiopharmaceuticals, were measured by means of potentiometry and spectrophotometry. Experimentally obtained pK values were compared with in silico predictions (Chemicalize/Marvin). The results demonstrate a considerable discrepancy between experimental and in silico values, with linear regression analysis showing intermediate correlation (R = 0.88, R = 0.82). This indicates that if one requires an accurate pK value, it is essential to experimentally assess it. This underscores the importance of experimentally determining pK values for accurate drug design and optimization. The study's data provide a valuable library of reliable experimental pK values for therapeutic drugs and radiopharmaceuticals, aiding researchers in the field.