Synthesis of fluorine-18-labeled biotin derivatives: biodistribution and infection localization

Recently there has been much interest in the exploitation of the high binding affinity of avidin/biotin as a means of targeting drugs and radionuclides for in vivo applications. We are interested in broadening the application of the avidin/biotin complex to PET. To this end we set out to prepare 18F-labeled biotin analogs.

Two 18F biotin derivatives, [3aS-(3a alpha,4 beta,6a alpha)]-hexahydro-2-oxo-1H-thieno[3,4- d]imidazole-4-(N-3-(1-[18F]fluoropropyl))pentanamide (1) and [3aS-(3a alpha,4 beta,6a alpha)]-tetrahydro-4-(5-(1-[18F]fluoropentyl)- 1H-thieno[3,4-d]imidazol-2(3H)-(2) were prepared with high specific activity (NCA) and evaluated for their potential in infection localization.

Compound 1 binds to avidin and the biodistribution of these derivatives were studied in Escherichia coli infected rats. Half of the infected rats were treated with avidin 24 hr prior to intravenous injection of the 18F-labeled biotin analogs. Biotin 1, without avidin pretreatment, showed a selectivity of 6.08 +/- 1.12 for infection compared to normal muscle. With avidin pretreatment, selectivity increased slightly, giving an infection to normal muscle ratio of 6.39 +/- 0.96. In contrast, the biodistribution of biotin 2 indicated more binding to normal muscle with an infection to normal muscle ratio of 0.58 +/- 0.07. This lack of selectivity illustrates the importance of the side-chain amide group in infection localization. There was some defluorination of 1 and 2, as evidenced by increased 18F bone uptake after 60 min: 2.94 +/- 0.37 and 1.17 +/- 0.21 %IG/g +/- s.d., respectively.

Biotin derivatives could be radiofluorinated with high specific activity. Biotin 1, is a potential positron tomography tracer for infection imaging.