(18)F-labeled Pyrazolo[1,5-a]pyrimidine Derivatives: Synthesis from 2,4-Dinitrobenzamide and Tosylate Precursors and Comparative Biological Evaluation for Tumor Imaging with Positron Emission Tomography

We previously reported (18)F-labeled pyrazolo[1,5-a]pyrimidine derivatives: 7-(2-[(18)F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([(18)F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[(18)F]fluoro-4-nitro- benzamide ([(18)F]2). Preliminary biodistribution experiments of both compounds showed s slow clearance rate from excretory tissues which warranted further investigation for tumor imaging with PET. Here we modified [(18)F]1 and [(18)F]2 by introducing polar groups such as ester, hydroxyl and carboxyl and developed three additional (18)F-18 labeled pyrazolo[1,5-a] pyrimidine derivatives: (3-Cyano-7-(2-[(18)F]fluoroethylamino)pyrazolo[1,5-a]-pyrimidin-5- yl)methyl acetate ([(18)F]3), 7-(2-[(18)F]fluoroethylamino)-5-(hydroxymethyl)pyrazolo[1,5-a]- pyrimidine-3-carbonitrile ([(18)F]4) and (S)-6-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7- ylamino)-2-(2-[(18)F]fluoro-4-nitrobenzamido)hexanoic acid ([(18)F]5). The radiolabeled probes were synthesized by nucleophilic substitution of the corresponding tosylate and nitro precursors with (18)F-fluoride. In Vitro studies showed higher uptake of [(18)F]3 and [(18)F]4 than that of [(18)F]5 by S180 tumor cells. In Vivo biodistribution studies in mice bearing S180 tumors showed that the uptake of both [(18)F]3 and [(18)F]4 in tumors displayed an increasing trend while the uptake of [(18)F]5 in tumor decreased through the course of the 120 min study. This significant difference in tumor uptake was also found between [(18)F]1 and [(18)F]2. Thus, we compared the biological behavior of the five tracers and reported the tumor uptake kinetic differences between 2-[(18)F]fluoroethylamino- and 2-[(18)F]fluoro-4-nitro- benzamidopyrazolo[1,5-a] pyrimidine derivatives.