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Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA).

ABSTRACT: Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different (99m)Tc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [(99m)Tc(CO)3](+) core (L8-L10), traditional NxSy-based chelating agents with varying charge and polarity for the (99m)Tc-oxo core (L11-L18), and a (99m)Tc-organohydrazine-labeled radioligand (L19). (99m)Tc(I)-Tricarbonyl-labeled [(99m)Tc]L8 produced the highest PSMA+ PC3 PIP to PSMA- PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of (99m)Tc-labeled radiopharmaceuticals targeting PSMA.

SUBMITTER: Ray Banerjee S

PROVIDER: S-EPMC3773988 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA).

Ray Banerjee Sangeeta S Pullambhatla Mrudula M Foss Catherine A CA Falk Alexander A Byun Youngjoo Y Nimmagadda Sridhar S Mease Ronnie C RC Pomper Martin G MG

Journal of medicinal chemistry 20130722 15

Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different (99m)Tc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumo ...[more]

PMID: 23799782

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Project description:BackgroundRadioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a 99mTc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa. However, commonly used [99mTc]Tc-PSMA-I&S exhibits slow whole-body clearance, thus hampering optimal tumor-to-background ratios (TBR) during surgery. We therefore aimed to develop novel 99mTc-labeled, PSMA-targeted radioligands with optimized pharmacokinetic profile to increase TBR at the time of surgery.MethodsThree 99mTc-labeled N4-PSMA ligands were preclinically evaluated and compared to [99mTc]Tc-PSMA-I&S. PSMA affinity (IC50) and internalization were determined on LNCaP cells. Lipophilicity was assessed by means of the distribution coefficient logD7.4 and an ultrafiltration method was used to determine binding to human plasma proteins. Biodistribution studies and static µSPECT/CT-imaging were performed at 6 h p.i. on LNCaP tumor-bearing CB17-SCID mice.ResultsThe novel N4-PSMA tracers were readily labeled with [99mTc]TcO4- with RCP > 95%. Comparable and high PSMA affinity was observed for all [99mTc]Tc-N4-PSMA-ligands. The ligands showed variable binding to human plasma and medium to low lipophilicity (logD7.4 - 2.6 to - 3.4), both consistently decreased compared to [99mTc]Tc-PSMA-I&S. Biodistribution studies revealed comparable tumor uptake among all [99mTc]Tc-N4-PSMA-ligands and [99mTc]Tc-PSMA-I&S, while clearance from most organs was superior for the novel tracers. Accordingly, increased TBR were achieved. [99mTc]Tc-N4-PSMA-12 showed higher TBR than [99mTc]Tc-PSMA-I&S for blood and all evaluated tissue. In addition, a procedure suitable for routine clinical production of [99mTc]Tc-N4-PSMA-12 was established. Labeling with 553 ± 187 MBq was achieved with RCP of 98.5 ± 0.6% (n = 10).ConclusionHigh tumor accumulation and favorable clearance from blood and non-target tissue make [99mTc]Tc-N4-PSMA-12 an attractive tracer for RGS, possibly superior to currently established [99mTc]Tc-PSMA-I&S. Its GMP-production according to a method presented here and first clinical investigations with this novel radioligand is highly recommended.

Project description:This report describes the synthesis of two cyclic RGD (Arg-Gly-Asp) conjugates, HYNIC-2PEG(4)-dimer (HYNIC = 6-hydrazinonicotinyl; 2PEG(4)-dimer = E[PEG(4)-c(RGDfK)](2); and PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and HYNIC-3PEG(4)-dimer (3PEG(4)-dimer = PEG(4)-E[PEG(4)-c(RGDfK)](2)), and evaluation of their (99m)Tc complexes [(99m)Tc(HYNIC-2PEG(4)-dimer)(tricine)(TPPTS)] ((99m)Tc-2PEG(4)-dimer: TPPTS = trisodium triphenylphosphine-3,3',3''-trisulfonate) and [(99m)Tc(HYNIC-3PEG(4)-dimer)(tricine)(TPPTS)] ((99m)Tc-3PEG(4)-dimer) as novel radiotracers for imaging integrin alpha(v)beta(3) expression in athymic nude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. The integrin alpha(v)beta(3) binding affinities of RGD peptides were determined by competitive displacement of (125)I-c(RGDyK) on U87MG glioma cells. It was found that the two PEG(4) linkers between RGD motifs in HYNIC-2PEG(4)-dimer (IC(50) = 2.8 +/- 0.5 nM) and HYNIC-3PEG(4)-dimer (IC(50) = 2.4 +/- 0.7 nM) are responsible for their higher integrin alpha(v)beta(3) binding affinity than that of HYNIC-PEG(4)-dimer (PEG(4)-dimer = PEG(4)-E[c(RGDfK)](2); IC(50) = 7.5 +/- 2.3 nM). Addition of extra PEG(4) linker in HYNIC-3PEG(4)-dimer has little impact on integrin alpha(v)beta(3) binding affinity. (99m)Tc-2PEG(4)-dimer and (99m)Tc-3PEG(4)-dimer were prepared in high yield with >95% radiochemical purity and the specific activity of >10 Ci/mumol. Biodistribution studies clearly demonstrated that PEG(4) linkers are particularly useful for improving the tumor uptake and clearance kinetics of (99m)Tc-2PEG(4)-dimer and (99m)Tc-3PEG(4)-dimer from noncancerous organs. It was also found that there was a linear relationship between the tumor size and radiotracer tumor uptake expressed as %ID (percentage of the injected dose) in U87MG glioma and MDA-MB-435 breast tumor models. The blocking experiment showed that the tumor uptake of (99m)Tc-2PEG(4)-dimer is integrin alpha(v)beta(3)-mediated. In the metabolism study, (99m)Tc-2PEG(4)-dimer had high metabolic stability during its excretion from renal and hepatobiliary routes. (99m)Tc-3PEG(4)-dimer also remained intact during thee excretion from the renal route, but, had approximately 30% metabolism during the excretion from the hepatobiliary route. Planar imaging studies in U87MG glioma and MDA-MB-435 breast tumor models showed that the tumors of approximately 5 mm in diameter could be readily visualized with excellent contrast. Thus, (99m)Tc-3PEG(4)-dimer is a very promising radiotracer for the early detection of integrin alpha(v)beta(3)-positive tumors, and may have the potential for noninvasive monitoring of tumor growth or treatment efficacy.

Project description:BackgroundPSMA expression in the prostate epithelium is controlled by a cis-element, PSMA enhancer (PSME). PSME contains multiple binding sites for Sox proteins, and in this study, we identified Sox7 protein as a negative regulator of PSMA expression through its interaction with PSME.MethodsThe statistical correlation between Sox7 and PSMA mRNA expression was evaluated using five prostate cancer studies from cBioportal. In vitro and in vivo interaction between Sox7 and PSME was evaluated by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assay. Synthetic oligonucleotides were generated to define the sites in PSME that interact with Sox7 protein. Sox7 mutants were generated to identify the region of this protein required to regulate PSMA expression. Sox7 was also stably expressed in LNCaP/C4-2 and 22Rv1 cells to validate the regulation of PSMA expression by Sox7 in vivo.ResultsSox7 mRNA expression negatively correlated with PSMA/FOLH1 and PSMAL/FOLH1B mRNA expression in Broad/Cornell, TCGA and MSKCC studies, but not in two studies containing only metastatic prostate tumors. PC-3 cells mostly expressed the 48.5 KDa isoform 2 of Sox7, and the depletion of this isoform did not restore PSMA expression. Ectopic expression of canonical, wild-type Sox7 in C4-2 and 22Rv1 cells suppressed PSMA protein expression. ChIP assay revealed that canonical Sox7 protein preferentially interacts with PSME in vivo, and EMSA identified the SOX box sites #2 and #4 in PSME as required for its interaction. Sox7 was capable of directly binding to PSME and suppressed PSME-mediated transcription. The NLS regions of Sox7, but not its β-catenin interacting motif, are essential for this suppressing activity. Furthermore, restoration of wild-type Sox7 expression but not Sox7-NLS mutant in Sox7-null prostate cancer cell lines suppressed PSMA expression.ConclusionsThe inactivation of canonical Sox7 is responsible for the upregulated expression of PSMA in non-metastatic prostate cancer.

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Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA).

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Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA).

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