A Pyropheophorbide Analogue Containing a Fused Methoxy Cyclohexenone Ring System Shows Promising Cancer-Imaging Ability

Abstract

Herein we report the synthesis, photophysical properties, positron emission tomography (PET) imaging and photodynamic therapy (PDT) efficacy of methyl 3-(1'-m-iodobenzyloxy)ethyl-3-devinyl-verdin 4 (with or without the ¹²⁴ I isotope). The PET imaging ability and ex vivo biodistribution of [¹²⁴ I]4 were compared with the well-studied methyl [3-(¹²⁴ 1'-m-iodobenzyloxy)ethyl]-3-devinyl-pyropheophorbide-a methyl ester (PET-ONCO or [¹²⁴ I]2) and [¹⁸ F]fluorodeoxyglucose ([¹⁸ F]FDG) in BALB/c mice bearing colon-26 tumors. Whole-body PET images of [¹²⁴ I]4 containing a fused methoxy cyclohexenone ring system showed excellent tumor contrast with time (72>48>24 h post-injection). Ex vivo biodistribution results indicate that relative to the current clinical standard [¹⁸ F]FDG and [¹²⁴ I]2 in 2 % ethanol formulation, [¹²⁴ I]4, at the same radioactive dose (25 μCi per mouse), showed higher tumor uptake at 24 h post-injection and longer tumor retention. In biological environments, compound 4 showed lower fluorescence and lower singlet oxygen yield than 2, which is possibly due to higher aggregation caused by the presence of a fused cyclohexenone ring system, resulting in limited in vitro/in vivo PDT efficacy. Therefore, the chlorophyll-a analogue [¹²⁴ I]4 provides easy access to a novel PET imaging agent (with no skin phototoxicity) to image cancer types-brain, renal carcinomas, pancreas-in which [¹⁸ F]FDG shows limitations.

Keywords: photodynamic therapy; photosensitizers; positron emission tomography; reactive oxygen species; relative uptake volume.