In vivo SPECT imaging of [¹²³I]-labeled pentamidine pro-drugs for the treatment of human African trypanosomiasis, pharmacokinetics, and bioavailability studies in rats.

Unlabelled: Pentamidine is an effective antiparasitic agent and approved drug for the treatment of African trypanosomiasis (sleeping sickness). However, pentamidine suffers from poor orally bioavailability and lacks central nervous system (CNS) delivery. Therefore its applicability is limited to intravenous or intramuscular treatment of the first stage of the African trypanosomiasis. For this reason, several new pentamidine pro-drugs have been developed with the aim of providing improved orally availability and CNS penetration.

Aim: this work aims to measure and to compare the distribution, bioavailability, and ability to cross the blood-brain barrier of [(123)I]-labeled pentamidine and its pro-drugs, N,N'-dihydroxypentamidine and N,N'‑bis(succinyloxy) pentamidine, using SPECT (single photon emission computed tomography) after intravenously and per orally administration in rats.

Methods: a total of 60 male Sprague Dawley rats were examined. Each [(123)I]-labeled substance (n=3) was applied to 12 rats (n=6 i.v. and n=6 orally). In two additional test series both [(123)I]iodopentamidine (n=6) and N,N'-bis(succinyloxy)-[(123)I]iodopentamidine (n=6) were administered orally together with the non-radioactive homologues. To evaluate the in vivo stability of the labeled compounds, [(123)I]NaI solution was administered intravenously (n=6) and orally (n=6). In vivo SPECT images were acquired after 30 min, 4h, and 24h and blood samples were taken over 24h. The SPECT images were fusioned with previously acquired magnetic resonance images. After the last SPECT the rats were perfused, sacrificed and the organ γ-radiation levels were determined with a γ-counter. Analysis and quantification of the reconstructed SPECT images was performed using the region of interest technique.

Results And Conclusion: the data showed a highly improved oral bioavailability of the [(123)I]-labeled pro-drugs compared to [(123)I]-labeled pentamidine. While [(123)I]iodopentamidine was mainly renally eliminated the pro-drugs were primarily metabolized in the liver and underwent biliary elimination. Considering pentamidine's nephrotoxicity this feature has to be seen as an advantage of the pro-drug principle. Moreover, a significantly higher concentration in the brain was detected after intravenous injection of N,N'-dihydroxy[(123)I]iodopentamidine compared to [(123)I]iodopentamidine. The feasibility of an effective treatment of second stage African trypanosomiasis, in which the parasites already infected the brain, with the herein investigated pro-drugs remains to be clarified with infected animals in additional in vivo studies.