Methyl 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a derivative), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophilic aromatic iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addition to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analogue of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 micromol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (lambda(max) 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.

The presence of cervical lymph node metastasis in patients with head and neck cancer is associated with an unfavorable prognosis. Reports vary as to whether various conventional radiographic studies, such as computed tomography (CT) and magnetic resonance imaging, confer an advantage over physical examination in the patient without clinical findings of cervical metastasis (N0). Positron emission tomography (PET) is a functional imaging modality that has recently been used for head and neck neoplasms. The use of PET in the evaluation of the N0-staged neck in 14 consecutive patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract is reported. Seven patients (50%) undergoing 13 neck dissections had pathologic evidence of disease. PET scans were positive in five patients with pathologically confirmed cervical metastasis. PET scans were negative in seven patients (11 neck dissections) with no pathologic evidence of disease. PET scans were positive for unilateral cervical metastasis in two of three patients with involvement of a single lymph node. PET scans were positive in two of three patients with more than two lymph nodes involved. PET had an accuracy of 100% in the eight patients with SCC of the oral cavity. In patients with oropharyngeal or hypopharyngeal carcinoma PET localized cervical metastasis in two of four patients with neck metastasis. In the patient with an N0-staged neck on clinical examination, PET was found to have an overall sensitivity of 78%, specificity of 100%, positive predictive value of 100%, negative predictive value of 88%, and accuracy of 92%. CT demonstrated sensitivity of 57%, specificity of 90%, positive predictive value of 80%, negative predictive value of 75%, and accuracy of 76%. PET showed a trend in increased accuracy (P = 0.11) over CT. PET appears to be a promising diagnostic aid that may be applied when evaluating the N0-staged neck, especially for SCC of the oral cavity.

The overall sensitivity, positive predictive value, and accuracy of PET were 100%, 80%, and 80%, respectively. The overall accuracy of radiography of the chest, computed tomography of the chest, and bronchoscopy was 70%, 90%, and 50%, respectively. The accuracy of PET over bronchoscopy was statistically significant (P<.05). PET appears to be a promising imaging modality for the detection of synchronous lung lesions in patients with negative findings on chest x-ray films.

In our present study, 3-(1′-m-iodobenzyloxyethyl) pyropheophorbide-a methyl ester 1, 3-(1′-m-iodobenzyloxyethyl)-172-{(2-deoxy)glucose} pyropheophorbide-a 2, and 3-(1′-m-iodo benzyloxyethyl)-172-{(1-deoxy)galactose} pyropheophorbide-a 3 were synthesized and converted into the corresponding 124I- labeled analogs by reacting the intermediate trimethyltin analogs with Na124I. Photosensitizers 1–3 were evaluated for the PDT efficacy in C3H mice bearing RIF tumors at variable doses and showed a significant long-term tumor cure. Among the compounds investigated, the non-carbohydrate analog 1 was most effective. These results were in contrast to the in vitro data, where compared to the parent analog the corresponding galactose-and glucose derivatives showed enhanced cell kill. Among the corresponding 124I-labeled in analogs, excellent tumor images were obtained from compound 1 both tumor models (RIF and Colon-26) and the best tumor contrast was observed at 72 h post injection. Conjugating a glucose moiety to photosensitizer 1 diminished its tumor uptake, whereas with time the corresponding galactose analog showed improved tumor contrast.

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Two positional isomers of purpurinimide; 3-[1'-(3-iodobenzyloxyethyl)] purpurin-18-N-hexylimide methyl ester 4 in which the iodobenzyl group is present at the top half of the molecule (position-3) and a 3-(1'-hexyloxyethy)purpurin-18-N-(3-iodo-benzylimide)] methyl ester 5, where the iodobenzyl group is introduced at the bottom half (N-substitued cyclicimide) of the molecule were derived from chlorophyll-a. The tumor uptake and phototherapeutic abilities of these isomers were compared with the pyropheophorbide analog 1 (lead compound). These compounds were then converted into the corresponding 124 I-labeled PET imaging agents with specific activity >1Ci/ μmole. Among the positional isomers 4 and 5, purpurinimide 5 showed enhanced imaging and therapeutic potential. However, the lead compound 1 derived from pyropheophorbide-a exhibited the best PET imaging and PDT efficacy. For investigating the overall lipophilicity of the molecule, the 3-O-hexyl ether group presnt at position-3 of purpurinimide 5 was replaced with a methyl ether substituent and the resulting product 10 showed improved tumor uptake, but due to its significantly higher uptake in liver, spleen and other organs, a poor tumor contrast in whole-body tumor imaging was observed.