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

• Published in: ChemMedChem 2019-08, Vol.14 (16), p.1503-1513
• Main Authors: Marko, Aimee J., Dukh, Mykhaylo, Patel, Nayan J., Missert, Joseph R., Ohulchanskyy, Tymish, Tabaczynski, Walter A., Ohkubo, Kei, Fukuzumi, Shunichi, Yao, Rutao, Sajjad, Munawwar, Pandey, Ravindra K.
• Format: Article
• Language: English
• Subjects: Brain; Cancer; Chlorophyll; Colon; Dosage; Ethanol; Fluorescence; Fluorine isotopes; Injection; Kidney cancer; Medical imaging; Neuroimaging; Pancreas; Pancreatic carcinoma; Photodynamic therapy; photosensitizers; Phototoxicity; Positron emission; Positron emission tomography; reactive oxygen species; relative uptake volume; Renal cell carcinoma; Singlet oxygen; Skin; Tomography; Tumors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900352

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 124I isotope). The PET imaging ability and ex vivo biodistribution of [124I]4 were compared with the well‐studied methyl [3‐(1241′‐m‐iodobenzyloxy)ethyl]‐3‐devinyl‐pyropheophorbide‐a methyl ester (PET‐ONCO or [124I]2) and [18F]fluorodeoxyglucose ([18F]FDG) in BALB/c mice bearing colon‐26 tumors. Whole‐body PET images of [124I]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 [18F]FDG and [124I]2 in 2 % ethanol formulation, [124I]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 [124I]4 provides easy access to a novel PET imaging agent (with no skin phototoxicity) to image cancer types—brain, renal carcinomas, pancreas—in which [18F]FDG shows limitations. Sensible sensitizers: We show that the photophysical properties, tumor specificity, uptake, imaging, and PDT efficacy of pyropheophorbide‐based compounds can be heavily influenced by the nature of the exocyclic ring present in the system. We observed encouraging tumor uptake and PET contrast in tumor‐bearing BALB/c mice by [124I]4, which contains a fused cyclohexenone ring. This provides easy access to a PET imaging agent with no skin phototoxicity for imaging cancer types in which the standard [18F]fluorodeoxyglucose has limitations.