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Cyclic RGD Peptides Incorporating Cycloalkanes: Synthesis and Evaluation as PET Radiotracers for Tumor Imaging.

ABSTRACT: Two new bicyclic arginine-glycine-aspartic acid (RGD) peptides, c(RGD-ACP-K) (1a) and c(RGD-ACH-K) (1b), incorporating the aminocyclopentane (ACP) and aminocyclohexane (ACH) carboxylic acids, respectively, were synthesized by grafting the aminocycloalkane carboxylic acids onto the tetra-peptide RGDK sequence. These peptides and their conjugates with DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid) (2a-b) exhibit high affinity toward U87MG glioblastoma cells. Their affinity is greater than that exhibited by c(RGDyK). Labeling these conjugates with radiometal (64)Cu resulted in high radiochemical yields (>97%) of the corresponding complexes, abbreviated as c(RGD-ACP-K)-DOTA-(64)Cu (3a) and c(RGD-ACH-K)-DOTA-(64)Cu (3b). Both 3a and 3b are stable for 24 h in human and mouse serums and show high tumor uptake, as observed by positron emission tomography (PET). Blocking experiments with 3a and 3b by preinjection of c(RGDyK) confirmed their target specificity and demonstrated their promise as PET radiotracers for imaging ???3-positive tumors.

SUBMITTER: Park JA

PROVIDER: S-EPMC4160751 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Cyclic RGD Peptides Incorporating Cycloalkanes: Synthesis and Evaluation as PET Radiotracers for Tumor Imaging.

Park Ji-Ae JA Lee Yong Jin YJ Lee Ji Woong JW Lee Kyo Chul KC An Gwang Il GI Kim Kyeong Min KM Kim Byung Il BI Kim Tae-Jeong TJ Kim Jung Young JY

ACS medicinal chemistry letters 20140710 9

Two new bicyclic arginine-glycine-aspartic acid (RGD) peptides, c(RGD-ACP-K) (1a) and c(RGD-ACH-K) (1b), incorporating the aminocyclopentane (ACP) and aminocyclohexane (ACH) carboxylic acids, respectively, were synthesized by grafting the aminocycloalkane carboxylic acids onto the tetra-peptide RGDK sequence. These peptides and their conjugates with DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid) (2a-b) exhibit high affinity toward U87MG glioblastoma cells. Their affinity is greater ...[more]

PMID: 25221652

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Project description:Integrin alpha(v)beta(3) plays a significant role in tumor angiogenesis and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand's factor, osteoponin, and adenovirus particles. Integrin alpha(v)beta(3) is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The restricted expression of integrin alpha(v)beta(3) during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Over the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as integrin alpha(v)beta(3)-targeted radiotracers. Significant progress has been made on their use for imaging integrin alpha(v)beta(3)-positive tumors by SPECT or PET. Among the radiotracers evaluated in preclinical tumor-bearing models, [18F]Galacto-RGD (2-[18F]fluoropropanamide c(RGDfK(SAA); SAA = 7-amino-L-glyero-L-galacto-2,6-anhydro-7-deoxyheptanamide) and [18F]-AH111585 are currently under clinical investigation for visualization of integrin alpha(v)beta(3) expression in cancer patients. However, their low tumor uptake, high cost, and lack of preparative modules for routine radiosynthesis will limit their continued clinical application. Thus, there is a continuing need for more efficient integrin alpha(v)beta(3)-targeted radiotracers that are readily prepared from a kit formulation without further postlabeling purification. This article will focus on different approaches to maximize the targeting capability of cyclic RGD peptides and to improve the radiotracer excretion kinetics from noncancerous organs. Improvement of tumor uptake and tumor-to-background ratios is important for early detection of integrin alpha(v)beta(3)-positive tumors and/or noninvasive monitoring of therapeutic efficacy of antiangiogenic therapy.

Project description:Recently, N-(4-18F-fluorobenzoyl)-interleukin-2 (18F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum 18F-fluoride-(restrained complexing agent)-IL2 (18F-AlF-RESCA-IL2) and 68Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 (68Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with 18F-FB-IL2. Methods: Radiolabeling of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. Results: 68Ga-Ga-NODAGA-IL2 and 18F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of 18F-AlF-RESCA-IL2 than of 18F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. 68Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than 18F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, 18F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. Conclusion: Production of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 is simpler and faster than that of 18F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts.

Dataset Information

Cyclic RGD Peptides Incorporating Cycloalkanes: Synthesis and Evaluation as PET Radiotracers for Tumor Imaging.

Publications

Cyclic RGD Peptides Incorporating Cycloalkanes: Synthesis and Evaluation as PET Radiotracers for Tumor Imaging.

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