Background

[PubMed]

The prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein that is present primarily in the prostate and is overexpressed during all stages of the androgen-insensitive or the metastatic cancer of this organ (1). In addition, PSMA is expressed at lower levels (compared to the prostate) in the neovasculature of some solid tumors (for details, see Elsasser-Beile et al. (1)). Because of its high expression during the development and progression of a malignancy, PSMA is considered to be a good target for the imaging and treatment of prostate cancer (2). Several investigators have reported the use of radio-halogenated (e.g., ¹⁸F, ¹²⁵I, etc.) and ^99mTc-labeled small molecule inhibitors for the imaging of PSMA (3). Among these radionuclides, ¹⁸F is the most frequently used to label diverse positron emission tomography (PET) agents for diagnostic imaging because its addition to a molecule (usually by the replacement of a hydrogen atom) does not alter its chemical properties; however, due to its short half-life (~110 min), an on-site cyclotron is needed to produce this radio-halogen (4). Recently ⁶⁸Ga (half-life, ~68 min) has been suggested to be a suitable alternative to the use of ¹⁸F for the production of PET imaging probes because ⁶⁸Ga is easy to produce with a ⁶⁸Ge/⁶⁸Ga generator system that does not have to be on-site. However, it is necessary to mention that currently no ⁶⁸Ge/⁶⁸Ga generator system has been approved by the United States Food and Drug Administration (Eckelman: personal communication). In addition, ⁶⁸Ga has been successfully used by some investigators to study cancer and tumor biology (4, 5). On the basis of these observations, and as an extension of their earlier work (for references, see Banerjee et al. (3)), Banerjee et al. developed two ⁶⁸Ga-labeled, urea-based inhibitors of PSMA ([⁶⁸Ga]-labeled 2-{3-[5-(7-{1-benzyloxycarbonyl-5-[2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraazacyclododec-1-l)acetylamino]pentylcarbamoyl}-heptanoylamino)-1-carboxypentyl]ureido}pentanedioic acid ([⁶⁸Ga]3) and [⁶⁸Ga]-labeled 2-[3-(1-carboxy-5-{7-[5-carboxy-5-(3-phenyl-2-{3-phenyl-2-[2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraazacyclododec-1-l)acetylamino]propionylamino}propionylamino)pentylcarbamoyl]heptanoylamino}pentyl)

ureido]pentanedioic acid ([⁶⁸Ga]6)) and evaluated them for biodistribution and the imaging of PSMA-expressing tumors in nude mice (3). This chapter details the results obtained with [⁶⁸Ga]3. Results obtained with [⁶⁸Ga]6 are presented in a separate chapter of MICAD (www.micad.nih.gov) (6).

Synthesis

[PubMed]

The synthesis of [⁶⁸Ga]3 has been described in detail by Banerjee et al. (3). The radiochemical yield and purity of the labeled compound were reported to be 76.2% and >99.0%, respectively. The retention time of [⁶⁸Ga]3 on analytical high-performance liquid chromatography (HPLC) was 25.0 min compared with a retention time of 22.5 min for [⁶⁸Ga]6. The specific activity of [⁶⁸Ga]3 was reported to be between 3.0 and 6.0 MBq/nmol (81 and 162 μCi/nmol). After purification, the radiochemical was dried under vacuum and diluted in 0.9% saline to the desired tracer concentration before use in biodistribution and imaging studies. The stability of [⁶⁸Ga]3 under in vitro or in vivo conditions was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Using unlabeled 3 and [⁶⁸Ga]3 in a fluorescence-based PSMA inhibition assay, the inhibitory concentrations of these compounds were reported to be 2.9 and 29.0 nM, respectively (3). In comparison, the PSMA inhibitory concentrations for unlabeled 6 and [⁶⁸Ga]6 were 1.23 and 0.44 nM, respectively.

Using a 1-octanol/water system, the partition coefficient of [⁶⁸Ga]3 was determined to be −3.9, which was similar to that of [⁶⁸Ga]6 (3). This indicated that both radiolabeled compounds were lipophilic (3). On the basis of the HPLC analysis reported above, [⁶⁸Ga]6 appeared to have a slightly higher lipophilicity than [⁶⁸Ga]3.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

NIH Support

These studies were funded by National Institutes of Health grants R01CA134675 and U24 CA92871.

References

1.

Elsasser-Beile U., Buhler P., Wolf P. Targeted therapies for prostate cancer against the prostate specific membrane antigen. Curr Drug Targets. 2009;10(2):118–25. [PubMed: 19199907]

2.

Dijkgraaf I., Boerman O.C. Radionuclide imaging of tumor angiogenesis. Cancer Biother Radiopharm. 2009;24(6):637–47. [PubMed: 20025543]

3.

Banerjee S.R., Pullambhatla M., Byun Y., Nimmagadda S., Green G., Fox J.J., Horti A., Mease R.C., Pomper M.G. 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer. J Med Chem. 2010;53(14):5333–41. [PMC free article: PMC3341619] [PubMed: 20568777]

4.

Fani M., Andre J.P., Maecke H.R. 68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals. Contrast Media Mol Imaging. 2008;3(2):67–77. [PubMed: 18383558]

5.

Holland J.P., Williamson M.J., Lewis J.S. Unconventional nuclides for radiopharmaceuticals. Mol Imaging. 2010;9(1):1–20. [PMC free article: PMC4962336] [PubMed: 20128994]

6.

Chopra, A., [68Ga]-Labeled 2-[3-(1-Carboxy-5-{7-[5-carboxy-5-(3-phenyl-2-{3-phenyl-2-[2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraazacyclododec-1-l)acetylamino]propionylamino}propionylamino)pentylcarbamoyl]heptanoylamino}pentyl)ureido]pentanedioic Acid. Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current. [PubMed: 21249764]