Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin αvβ3 PET imaging. Eur J Nucl Med Mol Imaging

Department of Radiology, Biophysics & Bio-X, Stanford University, Stanford, CA 94305, USA.
European Journal of Nuclear Medicine (Impact Factor: 5.38). 06/2009; 36(6):947-57. DOI: 10.1007/s00259-008-1045-1
Source: PubMed


Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. (18)F-labeled RGD analogs ([(18)F]-AH111585 and [(18)F]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted (68)Ga (t(1/2) = 68 min) for PET imaging of integrin alpha(v)beta(3) expression in tumor xenograft models.
The two new cyclic RGD dimers, E[PEG(4)-c(RGDfK)](2) (P(4)-RGD2, PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly(3)-c(RGDfK)](2) (G(3)-RGD2, G(3) = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for (68)Ga labeling. The microPET imaging and biodistribution of the (68)Ga labeled RGD tracers were investigated in integrin alpha(v)beta(3)-positive tumor xenografts.
The new RGD dimers with the Gly(3) and PEG(4) linkers showed higher integrin alpha(v)beta(3) binding affinity than no-linker RGD dimer (RGD2). NOTA-G(3)-RGD2 and NOTA-P(4)-RGD2 could be labeled with (68)Ga within 30 min with higher purity (>98%) and specific activity (8.88-11.84 MBq/nmol). Both (68)Ga-NOTA-P(4)-RGD2 and (68)Ga-NOTA-G(3)-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than (68)Ga-NOTA-RGD2.
Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin alpha(v)beta(3) expression in cancer patients is warranted.

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    • "Myotarg, now withdrawn, and Adcetris) are also indicated for disseminated leukemias or lymphomas, though some designed to target solid tumors are in clinical trials [13]. With radiolabeled peptides, methods to improve the targeting include sequence alteration [14]–[16], multivalency to increase affinity [17]–[20], increasing hydrophilicity to decrease nonspecific organ uptake [21]–[23], and the co-injection of amino acids to limit renal uptake [24]. "
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    ABSTRACT: Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In(3+)), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or IV methods was assessed by surface fluorescence, biodistribution of [(111)In] RGD and [(111)In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111)In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by IV). The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "oblastoma xenograft model ( Li et al . , 2008 ) . The monomer and dimer displayed similar tumor - to - normal tissue ratios and the dimer had greater absolute tumor uptake . The tetramer had the highest tumor uptake , but a much lower tumor - to - kidney ratio . The same group extended the study by adding a PEG 4 or Gly 3 linker to the RGD dimer ( Liu et al . , 2009a ) and found that both linkers significantly increased integrin binding affinity and tumor uptake compared to the non - linked dimer . They also found that the PEG 4 - linked 68 Ga radiotracer has similar imaging properties as 18 F - FAl - NOTA - PRGD2 and 18 F - FPPRGD2 ( Lang et al . , 2011 ) . 68 Ga and 111 In - labeled RGD derivative"
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    ABSTRACT: (68)Gallium-PET ((68)Ga-PET) agents have significant clinical promise. The radionuclide can be produced from a (68)Ge/(68)Ga generator on site and is a convenient alternative to cyclotron-based PET isotopes. The short half-life of (68)Ga permits imaging applications with sufficient radioactivity while maintaining patient dose to an acceptable level. Furthermore, due to superior resolution, (68)Ga-PET agents have the ability to replace current SPECT agents in many applications. This article outlines the upcoming agents and challenges faced during the translational development of (68)Ga agents.
    Full-text · Article · Oct 2012 · Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine
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    • "Dimerization is a suitable methodology to enhance the binding properties of tumor-targeting tracers. For example, cyclic RGD dimers, such as E[c(RGDfK)]2, were developed as diagnostic and therapeutic radiotracers with improved binding and imaging properties [27,41]. However, the improvement of binding capacity by dimerization is often accompanied by higher kidney or liver uptake of the tracer [27]. "
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    ABSTRACT: Background Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu‐ureido‐Lys via the 68Ga chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics. Methods The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu‐ureido‐Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts. Results Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5). Conclusions The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.
    Full-text · Article · Jun 2012 · EJNMMI Research
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