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Radiochemical Synthesis and Evaluation of 13N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas.

ABSTRACT: The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported selectivity of 5-ALA, a new positron emission tomography imaging probe was developed by reacting methyl 5-bromolevulinate with [13N] ammonia. The radiotracer, [13N] 5-ALA, was produced in high radiochemical yield (65%) in 10 min and could be purified using only solid phase cartridges. In vivo testing in rats bearing intracranial 9L glioblastoma showed peak tumor uptake occurred within 10 min of radiotracer administration. Immunohistochemical staining and fluorescent imaging was used to confirm the tumor location and accumulation of the tracer seen from the PET images. The quick synthesis and rapid tumor specific uptake of [13N] 5-ALA makes it a potential novel clinical applicable radiotracer for detecting and monitoring tumors noninvasively.

SUBMITTER: Pippin AB

PROVIDER: S-EPMC5733259 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Radiochemical Synthesis and Evaluation of 13N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas.

Pippin Adam B AB Voll Ronald J RJ Li Yuancheng Y Wu Hui H Mao Hui H Goodman Mark M MM

ACS medicinal chemistry letters 20171115 12

The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported selectivity of 5-ALA, a new positron emission tomography imaging probe was developed by reacting methyl 5-bromolevulinate with [13N] ammonia. The radiotracer, [13</s ...[more]

PMID: 29259740

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Project description:Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68Ga-labeled FAPI dimer, 68Ga-DOTA-2P(FAPI)2, to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods: 68Ga-DOTA-2P(FAPI)2 was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of 68Ga-DOTA-2P(FAPI)2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68Ga-FAPI-46 and 68Ga-DOTA-2P(FAPI)2 was performed on 3 cancer patients. Results: 68Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of 68Ga-DOTA-2P(FAPI)2 was approximately 2-fold stronger than that of 68Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68Ga-DOTA-2P(FAPI)2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of 68Ga-DOTA-2P(FAPI)2 than of 68Ga-FAPI-46 in all tumor lesions (SUVmax, 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion: 68Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared with 68Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.

Project description:IntroductionMalignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET).MethodsA small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells.ResultsEnzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors.ConclusionsThese data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.

Project description:A novel recombinant disintegrin, vicrostatin (VCN), displays high binding affinity to a broad range of human integrins in substantial competitive biological advantage over other integrin-based antagonists. In this study, we synthesized a new 64Cu-labeled VCN probe and evaluated its imaging properties for prostate cancer in PC-3 tumor-bearing mice. Macrocyclic chelating agent 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosine (DiAmSar) was conjugated with PEG unit and followed by coupling with VCN. The precursor was then radiolabeled with positron emitter 64Cu (t1/2 = 12.7 h) in ammonium acetate buffer to provide 64Cu-Sar-PEG-VCN, which was subsequently subjected to in vitro studies, small animal PET, and biodistribution studies. The PC-3 tumor-targeting efficacy of 64Cu-Sar-PEG-VCN was compared to a cyclic RGD peptide-based PET probe (64Cu-Sar-RGD). 64Cu labeling was achieved in 75% decay-corrected yield with radiochemical purity of > 98%. The specific activity of 64Cu-Sar-PEG-VCN was estimated to be 37 MBq/nmol. MicroPET imaging results showed that 64Cu-Sar-PEG-VCN has preferential tumor uptake and good tumor retention in PC-3 tumor xenografts. As compared to 64Cu-Sar-RGD, 64Cu-Sar-PEG-VCN produces higher tumor-to-muscle (T/M) imaging contrast ratios at 2 h (4.66 ± 0.34 vs. 2.88 ± 0.46) and 24 h (4.98 ± 0.80 vs. 3.22 ± 0.30) post-injection (pi) and similar tumor-to-liver ratios at 2 h (0.43 ± 0.09 vs. 0.37 ± 0.04) and 24 h (0.57 ± 0.13 vs. 0.52 ± 0.07) pi. The biodistribution results were consistent with the quantitative analysis of microPET imaging, demonstrating good T/M ratio (2.73 ± 0.36) of 64Cu-Sar-PEG-VCN at 48 h pi in PC-3 tumor xenografts. For both microPET and biodistribution studies at 48 h pi, the PC-3 tumor uptake of 64Cu-Sar-PEG-VCN is lower than that of 64Cu-Sar-RGD. 64Cu-Sar-PEG-VCN has the potential for in vivo imaging of prostate cancer with PET, which may provide a unique non-invasive method to quantitatively localize and characterize prostate cancer.

Dataset Information

Radiochemical Synthesis and Evaluation of 13N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas.

Publications

Radiochemical Synthesis and Evaluation of <sup>13</sup>N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas.

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