Aboagye, E. O.

Baguley, B. C.

Brady, F.

Brown, G. D.

Denny, W. A.

Gamage, S. A.

Luthra, S. K.

Myers, R.

Osman, S.

Price, P. M.

Rowlinson-Busza, G.

The tricyclic carboxamide N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a DNA-intercalating agent capable of inhibiting both topoisomerases I and II and is currently in Phase II clinical trial. Many related analogues have been developed, but despite their potent in vitro cytotoxicities, they exhibit poor extravascular distribution. As part of an ongoing drug development program to obtain related "minimal intercalators" with lower DNA association constants, we have compared the biodistribution and metabolite profiles of the prototype compound, DACA, with three analogues to aid rational drug selection. All of these compounds share a common structural feature, N-dimethyl side chain, which was radiolabeled with the positron-emitting radioisotope, carbon-11. This strategy was selected because it allows promising candidates emerging from preclinical studies in animals to be evaluated rapidly in humans using positron emission tomography (PET). The acridine DACA, the phenazine SN 23490, the pyridoquinoline SN 23719, and the dibenzodioxin SN 23935 were found to be cytotoxic in in vitro assays with an IC50 of 1.4-1.8 μM, 0.4-0.6 μM, 1.3-1.6 μM, and 24-36 μM, respectively, in HT29, U87MG, and A375M cell lines. Ex vivo biodistribution studies with carbon-11 radiolabeled compounds in mice bearing human tumor xenografts showed rapid clearance of 11C-radioactivity (parent drug and metabolites) from blood and the major organs. Rapid hepatobiliary clearance and renal excretion were also observed. There was low 

The University of Manchester - Institutional Repository

Comparative biodistribution and metabolism of carbon-11-labeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and DNA-intercalating analogues

Comparative biodistribution and metabolism of carbon-11-labeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and DNA-intercalating analogues

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