своевременная диагностика и терапия данного заболевания до сих пор являются нерешенной клинической задачей. По данным на 2011 г., заболе- ваемость раком простаты в России составила 10,7% (40 тыс. первичных случаев) мужского населения, причем в 60% случаев заболевание диа- гностировали на поздней (III–IV) стадии, когда неизбежен процесс активного роста и распространения метастазов. Методы анатомической визуализации при диагностике данного заболевания имеют низкую чувствительность и специфичность. Методы метаболической визуализации, использующие в качестве маркера простатспецифический антиген (ПСА), также малоэффективны. В качестве маркера для диагностики и лечения метастатического рака простаты предлагается рассматривать простатспецифический мембранный антиген (ПСМА). За рубежом проходят клинические испытания наиболее перспективные диагностические радиофармпрепараты на основе малых пептидных молекул, моди- фицированных мочевиной, которые отличаются наибольшим сродством к ПСМА. Отличительной особенностью этих соединений является их благоприятная фармакокинетика, высокое и длительное накопление в опухоли и метастазах, быстрое выведение из организма. Ключевые слова: метастатический рак предстательной железы, простатспецифический мембранный антиген, радиофармпрепараты. (Для цитирования: Власова О.П., Герман К.Э., Крылов В.В., Петриев В.М., Эпштейн Н.Б. Новые радиофармпрепараты для диагности- ки и терапии метастатического рака предстательной железы на основе ингибиторов простатспецифического мембранного антигена. Вестник РАМН. 2015; 70 (3): 360–365. Doi: 10.15690/vramn.v70i3.1334)

1. Prostate-specific Inhibitors of Membrane Antigen as a
Base for Radiopharmaceuticals for Diagnostics and
Therapy of Prostate Cancer
German Konstantin a,b, Vlasova Oksanad, Petriev Vladimire, Obruchnikova Yana a,c ,
Krilov Vladimir, Epshtein Natalia, Tananaev Ivana, Myasoedov Borisa,
Afanasiev Andrey a,b, Kryzhovets Olga a,
a Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pt, Moscow GSP-1,
b Medical University REAVIZ, Krasnobogatyrskaya,2; Moscow, Russia
c Mendeleev Russian Chemical Technology University, Miusskaya sq.1, Moscow
d- MEPhI, Obninsk
•Corresponding author: guerman_k@mail.ru Dec 3, 14-50
3rd Japan-China Academic
Symp. on Nuclear Fuel Cycle
December 2-5, 2015

2. Prostate specific membrane
antigen as a candidate biomarkers
for diagnosis and therapy
• As a radiopharmaceutical for the diagnosis and
treatment of prostate cancer useful to consider
the PSMA, which is a membrane abusive and
glycoprotein produced in high concentrations in
the epithelial cells of healthy individuals and
patients with prostate cancer.
• PSMA is normally found in secreted prostate
epithelial cells, but very weakly expressed in cells
of other organs (kidney, salivary cancer, small
intestine), and practically does not occure in
benign prostatic cancer.

3. Consortium organigram
Direсtorate
A.N. Frumkin
Institute of Physical
Chemistry and
Electrochemistry RAS,
Moscow
Medical
Institute Reaviz,
Moscow branch,
Russia
Burnazyan Federal
Medical Biological
Center of FMBA,
Moscow, Russia
National Research
Nuclear University
MEPhI, Obninsk,
Russia
Medical Radiological
Research Center of
Ministry of Health of
Russia, Obninsk, Russia
A. I. Leipunsky Institute for
Physics and Power
Engineering, Obninsk,
Russia
Tc-99m for
prostate cancer
diagnostics and
Re-188 for treatment

4. A.N. Frumkin Institute of Physical
Chemistry and Electrochemistry RAS,
Moscow
Technetium chemistry laboratory
• K. German, Project CEO, Head of Tc
laboratory, PhD , Doc., Prof.
• A. Safonov, Deputy head of Tc laboratory, PhD
• Ya. Obruchnikova, PhD
• V. Tregubova, PhD student
• M. Glazkova
Innovation department
• V. Lebedev, General manager for innovations
Laboratory of new physical-chemical problems
• A. Tsivadze, Director of IPCE RAS, Academician
• A. Filyanin, liquid extraction group, PhD
• V. Tarasov, NMR analysis, Professor
Laboratory of substance radiation chemistry
• B. Ershov, Head of laboratory, corr. member
RAS, Professor
• E. Abkhalimov, PhD
• R. Solovov, PhD student
Laboratory of interphase boundaries and
electocatalysis
• V. Andreev, Head of laboratory, Professor
Laboratory of radioactive material analysis
• M. Grigoriev, Head of laboratory, Professor

5. Sci. review on New Radiopharmaceuticals Based on Prostate-Specific Inhibitors of
Membrane Antigen for Diagnostics and Therapy of Metastatic Prostate Cancer
by
O.P. Vlasova1, K.E. German2, V.V. Krilov3, V.M. Petriev3, N.B. Epstein4
• 1 State Scientifi c Centre of the Russian Federation ≪Institute for Physics and Power Engineering n.a. A.I. Leypunsky≫, Obninsk, Russian Federation
• 2 A.N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, Moscow, Russian Federation
• 3A. Cyb Scientifi c Research Centre of Radiology, Obninsk, Russian Federation
• 4 National Research Nuclear University MEPhI, Obninsk, Russian Federation
About 10.7% cases of prostate cancer were registered in Russia in 2011 (40 000 patients).
More than half of cancer cases were revealed in advanced (III–IV) stages when metastases
inevitably developed quickly. Clinical problem of early diagnostics and treatment of
metastatic prostate cancer is still not solved.
Anatomical imaging techniques have low sensitivity and specificity for the detection of this
disease.
Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are
also ineffective.
This article describes prostate-specific membrane antigens (PSMA) that are proposed as a
marker for diagnostics and therapy of prostate cancer.
The most promising PSMA-based radiopharmaceutical agent for diagnostics has been
developed and clinically tested in the European countries. These pharmaceuticals are based
on small peptide molecules modified with urea, and have the highest affinity to PSMA.
Favorable pharmacokinetics, rapid accumulation in the tumor and rapid excretion from the
body are beneficial features of these pharmaceuticals.
• Annals of the Russian Academy of Medical Sciences. 2015; 70 (3): 360–365. Doi:
10.15690/vramn.v70i3.1334) (Vestnik Rossiiskoi Akademii Meditsinskikh Nauk)

6. 99m Tc-labeled peptide inhibitor of
PSMA
• a new RFP is based on the peptide inhibitor of
PSMA ,
• labeled with 99mTc is developed for diagnosis
• and labeled with 188Re - for radionuclide
therapy.
• Results of the Studies (Phase I and II) showed
that these RFP quickly "discover" the tumor
and its metastases including in lymph nodes
and skeletal size less 1 cm [16-18].

7. • The main purpose of the Institute is to carry
out fundamental and applied scientific
research in various fields of physical chemistry,
electrochemistry, chemical resistance of
materials, radiochemistry and radiation
chemistry.

8. A. I. Leipunsky Institute for Physics and
Power Engineering, Obninsk, Russia
• O. Vlasova, N. Nerozin, Yu. Shevko, I. Zhuk
• multidisciplinary scientific organization,
conducting complex investigations of physical
and technical problems of nuclear science and
technology.

9. Medical Radiological Research Center
of Ministry of Health of Russia,
Obninsk, Russia
• V. Skvortsov, V. Petriev
• Mission: Development of concepts, regulatory
documents related to radiation safety of a human
and the environment, health security and
reduction of socioeconomic prejudice caused by
radiation.
• The Institute was founded in 1962 to develop and
improve methods of radiation diagnostics and
radiation therapy, prevention and treatment of
radiation injury, the study of the biological and
medical effects of ionizing radiation.

10. National Research Nuclear University
MEPhI, Obninsk, Russia
• N. Airapetova, N. Epshtein
• Development of analytical procedures
for quality control of
radiopharmaceuticals and staff training
• Mission: to generate, disseminate the use and to
preserve scientific knowledge aiming to address
global challenges of the XXI century, as well as to
provide innovative transformations in Russia
accompanying development of the country
competitiveness in the global energy and non-
energy high-tech markets.

11. Burnazyan Federal Medical Biological
Center of FMBA, Moscow, Russia
• G. Kodina, PhD, Department head
• A. Maruk, PhD, Laboratory Head
• Production of Tc-99m (for radiodiagnostics)
and Re-188 (for radiotherapy) isotopes and
preclinical medicine tests
• Fundamental and applied research in the field of radiation
medicine, radiobiology and radiation protection;
• Research in the field of biomedical technologies, radiopharmacy;
• Development of new radiation technologies (including photon
and neutron capture therapy);
• Research in the field of chemical and radiation safety in the use
of technology for special applications.

12. Medical Institute Reaviz,
Moscow branch, Russia
• K. German, Chair of Natural science, Professor
• A. Safonov, docent, PhD
• Ya. Obruchnikova, assistant prof., PhD
• V. Tregubova, PhD student
• Training of medical staff for modern medicine
“The main aim of Reaviz is the training of health care staff, of young people
who should become highly professional physicians in the nearest future. The
most important quality for these professionals should be the integration of the
greatest responsibility and the inner freedom of this profession, of scientific
research and practical achievements.” Rector of Samara Medical Institute
“REAVIZ”, Doctor of Medical Science, professor Nikolay A. Lyssov

13. What we intend to obtain
In the course of this project should be developed
• production technologies of 99mTc generators and high-
value 188Re generators with reduced transport index,
• technologies of 188Re concentration, development of
analytical methods for detection of radioactive and
chemical impurities in the 188Re preparation,
• quality assurance of 99mTc and 188Re generator eluates
in accordance with the requirements of potential
radiopharmaceuticals based on them, specifically binds
to the receptor tissue of prostate cancer.

14. What we already have
for radionuclide imaging
• 2-18F-fluoro-2-deoxy-D-glucose (FDG);
• 111In-7E11 antibody (ProstaScint);
• 18F-fluorodihydrotestosterone (18F-FDHT);
• radioacetate analogs;
• radiocholine analogs;
• anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic
acid (anti-[18F]FACBC)
Production of Tc-99m (for radiodiagnostics) and Re-188
(for radiotherapy) isotopes were improved with
optimized generator design aimed to high specific activity
production.

15. • Potential consumer of radiopharmaceuticals
(RPh): medical institutions at various levels,
cancer medical centers, cancer clinics, licensed to
work with sources of ionizing radiation and
equipped with diagnostic equipment, SPECT or
PET.
• Objects of RPh application: patients with the
disease of prostate cancer (about 30 thousand
pers. / year).
• Over the past few years in Russia approximately
40,000 new cases of prostate cancer per year
were recorded, and only for 30% of them
brachytherapy is performed with an efficiency of
75%

16. Effective diagnostics and therapy of
prostate cancer is an important issue
for Russia due to constantly increasing
number of decease cases herein.
Rational development of new radiopharmaceuticals
for the management of advanced and metastatic
prostate cancer requires an improved cooperation
of the organization thus involved. For this reason an
interdisciplinary consortium collaboration for the
development of radiopharmaceutical approach is
established with principle aim to improve the
situation within the 3 coming years.

17. The development of new radiopharmaceuticals
and generators for the management of
advanced prostate cancer will help to improve
the treatment of this disease in Russia.

18. • Special educational interdisciplinary program for
specialist training for technetium application to
prostate radiodiagnostics is elaborated.
• The development of new radiopharmaceuticals
and generators for the management of advanced
prostate cancer will help to improve the treatment
of this disease in Russia.
• Innovative character of this project requires special
attention on staff training.
• New technologies worked out by Igor Zhuk and
Yury Shevko (A.I. Leipunsky Institute for Physics
and Power Engineering, Obninsk, Russian
Federation) are to be used in this project

19. Thank you !