nach oben

Erschienen in:

04.06.2019 | Research Article

Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([¹²⁴I]IPAG)

verfasst von: Kishore K. Gangangari, András Váradi, Susruta Majumdar, Steven M. Larson, Gavril W. Pasternak, NagaVara Kishore Pillarsetty

Erschienen in: Molecular Imaging and Biology | Ausgabe 2/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of iodine-124-labeled IPAG ([¹²⁴I]IPAG) to image S1R-overexpressing tumors.

Procedures

[¹²⁴I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 10⁷ cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [¹²⁴I]IPAG to image tumors was evaluated in LNCaP tumor–bearing mice as well.

Results

[¹²⁴I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [¹²⁴I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor–bearing mice reveal that [¹²⁴I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [¹²⁴I]IPAG could be competitively inhibited by excess of IPAG and haloperidol.

Conclusions

[¹²⁴I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [¹²⁴I]IPAG. [¹²⁴I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.

Nur mit Berechtigung zugänglich

Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (1996) Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 93:8072–8077CrossRef

Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC (2016) Crystal structure of the human σ1 receptor. Nature 532:527–530CrossRef

Kim FJ, Schrock JM, Spino CM, Marino JC, Pasternak GW (2012) Inhibition of tumor cell growth by sigma1 ligand mediated translational repression. Biochem Biophys Res Commun 426:177–182CrossRef

Van Waarde A, Rybczynska A, K Ramakrishnan N et al (2010) Sigma receptors in oncology: therapeutic and diagnostic applications of sigma ligands. Curr Pharm Des 16:3519–3537CrossRef

Aydar E, Palmer CP, Djamgoz MB (2004) Sigma receptors and cancer possible involvement of ion channels. Cancer Res 64:5029–5035CrossRef

van Waarde A, Rybczynska AA, Ramakrishnan NK, Ishiwata K, Elsinga PH, Dierckx RAJO (2015) Potential applications for sigma receptor ligands in cancer diagnosis and therapy. Biochim Biophys Acta Biomembr 1848:2703–2714CrossRef

Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2:683–693CrossRef

James ML, Shen B, Zavaleta CL, Nielsen CH, Mesangeau C, Vuppala PK, Chan C, Avery BA, Fishback JA, Matsumoto RR, Gambhir SS, McCurdy CR, Chin FT (2012) New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects. J Med Chem 55:8272–8282CrossRef

Waterhouse RN, Collier TL (1997) In vivo evaluation of [¹⁸F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine: a selective sigma-1 receptor radioligand for PET. Nucl Med Biol 24:127–134CrossRef

10.

Toyohara J, Sakata M, Ishiwata K (2009) Imaging of sigma1 receptors in the human brain using PET and [¹¹C]SA4503. Cent Nerv Syst Agents Med Chem 9:190–196CrossRef

11.

Kranz M, Sattler B, Wüst N, Deuther-Conrad W, Patt M, Meyer P, Fischer S, Donat C, Wünsch B, Hesse S, Steinbach J, Brust P, Sabri O (2016) Evaluation of the enantiomer specific biokinetics and radiation doses of [¹⁸F] fluspidine—a new tracer in clinical translation for imaging of σ1 receptors. Molecules 21:1164CrossRef

12.

Kovács KJ, Larson AA (1998) Up-regulation of [³H]-DTG but not [³H](+)-pentazocine labeled σ sites in mouse spinal cord by chronic morphine treatment. Eur J Pharmacol 350:47–52CrossRef

13.

Everaert H, Bossuyt A, Flamen P et al (1997) Visualizing ocular melanoma using iodine-123-N-(2-diethylaminoethyl) 4-iodobenzamide SPECT. J Nucl Med 38:870PubMed

14.

John C, Bowen W, Saga T, Kinuya S, Vilner BJ, Baumgold J, Paik CH, Reba RC, Neumann RD, Varma VM (1993) A malignant melanoma imaging agent: synthesis, characterization, in vitro binding and biodistribution of iodine-125-(2-piperidinylaminoethyl) 4-iodobenzamide. J Nucl Med 34:2169–2175PubMed

15.

Nicholl C, Ashour M, Hull WE et al (1997) Pharmacokinetics of iodine-123-IMBA for melanoma imaging. J Nucl Med 38:127–133PubMed

16.

John CS, Bowen WD, Fisher SJ, Lim BB, Geyer BC, Vilner BJ, Wahl RL (1999) Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1′-piperidinyl) ethyl]-3-[¹²⁵I]iodo-4-methoxybenzamide (P[¹²⁵I]IMBA) for imaging breast cancer. Nucl Med Biol 26:377–382CrossRef

17.

John CS, Vilner BJ, Gulden ME, Efange SM, Langason RB, Moody TW, Bowen WD (1995) Synthesis and pharmacological characterization of 4-[¹²⁵I]-N-(N-benzylpiperidin-4-yl)-4-iodobenzamide: a high affinity σ receptor ligand for potential imaging of breast cancer. Cancer Res 55:3022–3027PubMed

18.

Pickett JE, Váradi A, Palmer TC, Grinnell SG, Schrock JM, Pasternak GW, Karimov RR, Majumdar S (2015) Mild, Pd-catalyzed stannylation of radioiodination targets. Bioorg Med Chem Lett 25:1761–1764CrossRef

19.

Kimes AS, Wilson AA, Scheffel U, Campbell BG, London ED (1992) Radiosynthesis, cerebral distribution, and binding of [¹²⁵I]-1-(p-iodophenyl)-3-(1-adamantyl)guanidine, a ligand for sigma binding sites. J Med Chem 35:4683–4689CrossRef

20.

Choenwald RD, Barfknecht CF (1995) Use of sigma receptor ligands as salivary gland stimulants. United States Patent 387:614

21.

van Waarde A, Jager PL, Ishiwata K, Dierckx RA, Elsinga PH (2006) Comparison of sigma-ligands and metabolic PET tracers for differentiating tumor from inflammation. J Nucl Med 47(1):150–154PubMed

Titel: Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG)
verfasst von: Kishore K. Gangangari
András Váradi
Susruta Majumdar
Steven M. Larson
Gavril W. Pasternak
NagaVara Kishore Pillarsetty
Publikationsdatum: 04.06.2019
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 2/2020
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-019-01369-8

Update Radiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([¹²⁴I]IPAG)