Synthesis of [18F]BODIPY: bifunctional reporter for hybrid optical/positron emission tomography imaging.
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ABSTRACT:
SUBMITTER: Hendricks JA
PROVIDER: S-EPMC3343182 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
Publications
Synthesis of [18F]BODIPY: bifunctional reporter for hybrid optical/positron emission tomography imaging.
Hendricks J Adam JA Keliher Edmund J EJ Wan Dongpeng D Hilderbrand Scott A SA Weissleder Ralph R Mazitschek Ralph R
Angewandte Chemie (International ed. in English) 20120404 19
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2011-11-01 | GSE21217 | GEO
Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.
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Project description:Positron emission tomography (PET) is a powerful technique for imaging biological pathways in vivo, particularly those that are key targets in disease processes. In contrast, fluorescence imaging has demonstrated to be a superior method for image-guided surgery, such as tumor removal. Although the integration of PET and optical imaging could provide an attractive strategy for patient management, there is a significant shortage of established platforms/methods for PET/optical probe construction. In this study, various reaction conditions were explored to develop a simple and fast method allowing for the introduction of [(18)F]-fluoride into BODIPY dyes. Through a systematic optimization of the reaction conditions, we found that BODIPY dyes, including commercial amine-reactive BODIPY succinimidyl esters, may be converted into their radioactive analogues in the matter of minutes via a (18)F-(19)F isotopic exchange reaction promoted by a Lewis acid such as SnCl4. An integrin-targeting RGD peptide was also conjugated with [(18)F]BODIPY® R6G , derived from the commercially available BODIPY® R6G fluorescent tag, to provide a [(18)F]-RGD conjugate in 82% yield. In vivo evaluation of this imaging probe showed a discernible tumor uptake in the U87MG xenograft model. The dual modality imaging properties of the probe was confirmed by ex vivo fluorescence and microPET imaging experiments. In summary, in the matter of minutes, BODIPY dyes were converted into their "hot" radioactive analogues via a (18)F-(19)F isotopic exchange reaction promoted by a Lewis acid. This approach, which can be applied to commercial BODIPY dyes, provides easy access to positron emission tomography/fluorescence dual modality imaging agents.
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Project description:BACKGROUND:To evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUVmax) at 60 min (SUVmax1) and SUVmax at 120 min (SUVmax2) (ΔSUVmax%) using dual time point 18F-fluorodeoxyglucose emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer. METHODS:Four hundred and sixty-four patients with primary breast cancer underwent 18F-FDG PET/CT for preoperative staging. ΔSUVmax% was defined as (SUVmax2 - SUVmax1) / SUVmax1 × 100. We explored the optimal cutoff value of SUVmax parameters (SUVmax1 and ΔSUVmax%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUVmax1 and ΔSUVmax% were analyzed by Cox's univariate and multivariate analyses. RESULTS:The optimal cutoff values of SUVmax1 and ΔSUVmax% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUVmax1 groups (P = 0.0003) and also between high and low ΔSUVmax% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUVmax1 was an independent prognostic factor (P = 0.0267) but ΔSUVmax% was not (P = 0.152). There was a weak correlation between SUVmax1 and ΔSUVmax% (P < 0.0001, R2 = 0.166). On combining SUVmax1 and ΔSUVmax%, the subgroups of high SUVmax1 and high ΔSUVmax% showed significantly worse prognosis than the other groups in terms of RFS (P = 0.0002). CONCLUSION:Dual time point 18F-FDG PET/CT evaluation can be a useful method for predicting relapse in patients with breast cancer. The combination of SUVmax1 and ΔSUVmax% was able to identify subgroups with worse prognosis more accurately than SUVmax1 alone.
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