Design and synthesis of an optical-PET bimodal imaging probe based on a NIR fluorophore and fluorine-18

Complete text of publication follows: Objectives: Among the ever-growing development of imaging probes, an increasing attention has been focused in the past few years on the synthesis of scaffolds exhibiting more than one imaging modality.1 Combination of two or more imaging modalities on a unique targeting vector allows to fully exploit each imaging asset. In this context, our group is involved in the conception and the synthesis of a probe combining PET and optical imaging modalities, a highly synergistic association with similar and compatible sensitivity. The functional and quantitative diagnosis of PET along with intraoperative imaging-guided surgery of Near Infrared Fluorophore (NIRF) could lead to promising imaging tools for both diagnostic and therapy. Methods: The designed probe relies on a scaffold functionalized with a fluorine-18 radionuclide as the PET emitter, a hepthamethine cyanine as the NIRF optical dye and an azide moiety which serves as an attachment point to the targeting vector. This versatile imaging tool was syn- the sized in a convergent synthesis sequence with a late introduction of the light sensitive cyanine. Fully automated radiosynthesis was developed and based on an aliphatic substitution with fluorine-18, leading to a radiolabeled PET-NIRF probe with a good radiochemical yield, ready to be functionalized with a targeting vector by CuAAC click reaction. Results: The tosyl-oxy-precursor and the non-radioactive reference were respectively synthesized in 7 and 6 steps with an overall yield of 18% and 33%. Both of those compounds could be obtained at a ≥100 mg scale from the commercial IR780 cyanine dye. A screening of temperature for the radiofluorination of the precursor was performed, resulting in a conversion of 55% at 100 C in DMSO with the K[¹⁸F]F/K222 complex without significant degradation. The fully automated radiosynthesis allows the production of the ¹⁸F-bimodal probe with a typical decay-corrected yield of 15% and 6.5 GBq (EOB) over a 97 min synthesis time. Quantitative conversion was observed for the CuAAC with an alkyne-functionalized PSMA, used as a targeting vector, in less than 10 min at 40 C. Conclusion: The synthesis and radiosynthesis of an original PET-NIRF bimodal scaffold was developed. With high activity concentration, this versatile scaffold could be conjugated to biologically relevant targeting vectors to initiate the development of PET-NIRF in vivo bimodal imaging