REVIEW OF PROSPECTIVE RADIOPHARMACEUTICALS BASED ON PROSTATE- SPECIFIC INHIBITORS OF MEMBRANE ANTIGEN FOR DIAGNOSTICS AND THERAPY OF METASTATIC PROSTATE CANCERтезисы доклада
Дата последнего поиска статьи во внешних источниках: 3 июля 2019 г.
Аннотация:Prostate cancer (PC) one of the most common oncological diseases. In Russia this disease
is found in 60% cases after diagnostics on late stage (3-4), when process of active growth of
cancer’s cells is inevitable. In 1/3 of patients PC was diagnostied with metastases already
present [1-3]. Metastases of prostate cancer are often detected in bone tissue (80-90 % from all
localizations), lymphatic nodes (10%), liver and lungs (2.5 %). This localization is nor favorable
for radical treatment. Most of this patients (about 60% from all PC cases) die within 1,5 – 2 years
from the moment when disease diagnosis was made. Nowdays about 40 thousand of the first case
PC are being registered per year in Russian Federation. Brachiotherapy efficiency is 75% effective
[2, 3]. Consequently in effect treatment metastatic PC – need about 30 thousand patients every
year only on territory of Russia.
Early diagnosis of post-surgical relapses, as well as widespread metastatic prostate cancer
and castration-resistant prostate cancer remains an unresolved problem. The complexity of early
diagnosis of metastatic foci of prostate cancer leads to a significant decrease in life expectancy of
patients after the initial treatment due to the occurrence of local and distant relapses. For example,
despite numerous screening programs, in the US, prostate cancer is the second leading cause of
death from cancer among men [4, 5].
Prostate-specific membrane antigen (PSMA) is a type II membrane protein is expressed in
all forms of prostate tissue, including neoplasms [6]. The expression of PSMA in cancer cells is
100-1000 times higher than in other tissues and normal prostate cells. It is important that the
intensity of PSMA expression increases with prevalent metastatic PC, and especially in castrationresistant
PC. Unlike PSA, PSMA is not found in the blood. Thus, PSMA is an ideal marker of
prostate cancer cells and an excellent target for radionuclide imaging and therapy [7-9]. Given this
fact, in the West, radiopharmaceutical kits (RPKs) were developed to visualize PC based on
targeted compounds that selectively bind to PSMA on the membrane cancer cells. 111In-capromab
was the first clinical radiopharmaceutical (RP) for visualization of PC. Despite good results of
visualization of the primary tumor, satisfactory data on the visualization of local and distant
metastases were not obtained. In addition, the compound was loosely bound to the PSMA receptor,
was slowly excreted from the body and therefore did not provide sufficient coefficients of
differential accumulation and, accordingly, a qualitative visualization of metastases [4, 8, 9]. Later,
improved RPs with 123I for diagnosis and 131I, 177Lu and 90Y for therapy were developed [7, 10].
However, in spite of the best results of preclinical and pilot clinical trials, in comparison with 111Incapromab,
these new RPs have not been clinically used since retained the deficiencies of labeled
antibodies: weak interaction with the PSMA receptor, a high background in the blood, and a long
waiting time for visualization. In 2009, small peptide molecules PSMA inhibitors characterized
by high selective affinity to PC were developed (e.g. (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-
4-[18F]methyl-L-cysteine[18F]DKPMMC)). These molecules, labeled with 18F, showed
satisfactory results in PET diagnostics of [7, 9].However, the most encouraging results were obtained by two groups of researchers (MIP
Cambridge, USA and DNM Heidelberg, Germany) using new small peptide molecules modified
with urea with the highest affinity for PSMA. Based on these compounds, new RPs for SPECT
(123I, 99mTc, 111In) and PET (18F, 68Ga, 64Cu) were studied. RPs for radionuclide therapy with 131I,
188Re, 177Lu, 90Y were studied as well. A distinguishing feature of these compounds is favorable
pharmacokinetics, a high and prolonged accumulation in tumor and metastases, rapid excretion
from the body, which provides high value of the differential accumulation factor, and high-quality
rendering of small tumor foci [10-12].
Then new 99mTc-PSMA and 188 Re-PSMA RPs were developed. The results of the clinical
studies showed that these RPs quickly visualize the tumor and its metastases, including ones in
lymph nodes and skeleton [10-12]. Currently, 68Ga and 177Lu PSMA-based radiopharmaceuticals
are being extensively studied [13], but also are being used in routine clinical practice in some
countries.References
1. Veliev EI, Sokolov EA, Ivkin EV. New in hormone therapy for prostate cancer. Practical
oncology. 2012; 13 (3): 151-155.
2. Korenev IV. Prostate scintigraphy with 99mTc-technetril in early preoptopic prostate cancer
diagnosis. Author's abstract. dis ... cand. honey. sciences. Chelyabinsk. 2009. 25 pp.
3. Khmara TG Informativity of modern methods of diagnosis of prostate cancer. Author's
abstract. dis ... cand. honey. sciences. Saratov. 2010. 26 pp.
4. Clinical recommendations of the European Association of Urology. Shiranova KA. M.
2011. 162 pp.
5. Cho SY, Gage KL, Mease RC et al. Biodistribution, Tumor Detection, and Radiation
Dosimetry of 18F DCFBC, a low-molecular-weight Inhibitor of Prostate Specific
Membrane Antigen, in Patients with Metastatic Prostate Cancer. J. Nucl. Med. 2012; 53:
1883-1891.
6. Chang SS. Overview of Prostate-Specific Membrane Antigen. Reviews in Urology.
2004;6(Suppl 10):S13-S18.
7. Osborne JR, Akhtar NH, Vallabhajosula Sh, Anand A, Deh K, Tagawa ST. Prostate
specific membrane antigen based imaging. Urol. Oncol. 2013; 31: 144-154.
8. Sardana G, Dowell B, Diamandis EP Emerging Biomarkers for the Diagnosis and
Prognosis of Prostate Cancer. Clin. Chemistry. 2008; 54 (12): 1951-1960.
9. Mease RC, Foss CA, Pomper MG. PET imaging in prostate cancer: focus on prostate
specific membrane antigen. Curr. Top. Med. Chem. 2013; 13 (8): 951-962.
10. Hillier SM, Maresca KP, Lu G, et al. 99mTc-Labeled Small Molecule Inhibitors of Prostate
Specific Membrane Antigen for Molecular Imaging of Prostate Cancer. J. Nucl. Med. 2013;
54: 1369-1376.
11. Pomper, MG, et al. Labeled inhibitors of prostate specific membrane antigen (PSMA)
biological evaluation, and use of imaging agents. U.S. Patent No. 9,694,091. 4 Jul. 2017.
12. Taira, Y, et al. Coordination-mediated synthesis of purification-free bivalent 99mTc-labeled
probes for in vivo imaging of saturable system. Bioconjugate chemistry. 2018; 29 (2) 459-
466.
13. Larenkov AA, Kodina GE. Radionuclide Diagnosis of Prostate Cancer: Positron Emission
Tomography with 68Ga-PSMA Inhibitors and Their Pharmaceutical Development. Medical
Radiology and Radiation Safety. 2017; 62 (6): 58-74.
The work was carried out with partial funding by the Ministry of Science and
Higher Education of the Russian Federation (Project No. AAAAA16-
116110910010-3)
