Technetium-99m-d,l-HM-PAO, the development of a new class of 99mTc-labeled tracers: an overview.

Abstract

For several years, it has been clear that the de­ velopment of a 99mTc-labeled tracer that is retained in the brain in proportion to local cerebral blood flow (rCBF) would be of considerable medical in­ terest, since it would allow CBP imaging to become a routine clinical procedure using single photon emission tomography (SPECT). Several laborato­ ries have devoted resources and chemical ingenuity to achieve this aim. The development of a chem­ ical microsphere class of blood flow imaging agents was spurred by the advent of iodine123-labeled amines pioneered by the work of Winchell and co-workers with iodoisopropylam­ phetamine (IMP) (Winchell et aI., 1980) and by Kung and co-workers with hydroxyisopropyldi­ amine (HIPDM) (Kung and Blau, 1980). 99mTc has better imaging and dosimetry charac­ teristics than iodine-123. However, the basic prob­ lem with 99mTc is how to incorporate the radionu­ elide into an organic molecule so that a lipophilic complex is formed that rapidly crosses the blood­ brain barrier (BBB) and is retained in the brain. Most work has centered on derivatives of propylene amine oxime (PnAO or simply PAO) proposed by Troutner et al. (1983) and on the diaminodithiols (DADT, also called BAT for bisaminoethanethiol) proposed independently by Kung et al. (1983) and Ravert et al. (1983). These initial efforts were suc­ cessful in that rapid uptake into the brain was dem­ onstrated with some but not all of these lipophilic compounds. A major problem with the first gen­ eration 99mTc brain imaging compounds was that some of them demonstrated either a high degree of plasma protein binding and did not appreciably cross the BBB or, if they did cross the BBB, they were not retained due to rapid back-diffusion (brain to blood). Two years later and after extensive re­ search with more than 100 PnAO derivatives, Neir­ inckx and collaborators succeeded in finding a hex­ amethyl derivative of propylene amine oxime