Reaction Evaluation Of Positron Emitter ( Zirconium89) Under Selected Region Of Three Alpha Particles

Description

ABSTRACT

Molecular imaging—and especially Positron Emission Tomography (PET)—is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, ⁸⁹Zr (t_1/2 = 3.27 days and mean E_β+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of ⁸⁹Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges.

TABLE OF CONTENTS

COVER PAGE

TITLE PAGE

APPROVAL PAGE

DEDICATION

ACKNOWELDGEMENT

ABSTRACT

CHAPTER ONE

• INTRODUCTION
• BACKGROUND OF THE PROJECT
• AIM OF THE STUDY
• SCOPE OF THE PROJECT

CHAPTER TWO

LITERATURE REVIEW

• OVERVIEW OF THE ZIRCONIUM
• ISOTOPES OF ZIRCONIUM
• SOURCES OF ALPHA PARTICLES
• MECHANISM OF PRODUCTION IN ALPHA DECAY
• MAJOR FORMS OF RADIOACTIVITY
• POSITRON EMISSION (Β⁺ DECAY) AND ELECTRON CAPTURE

CHAPTER THREE

METHODOLOGY

• RADIOLABELING OF BIOACTIVE MOLECULES WITH ⁸⁹ZR
• DESFERRIOXAMINE B INTO BIOACTIVE MOLECULES

CHAPTER FOUR

• 89Zr-LABELED BIOACTIVE COMPOUNDS
• PEPTIDES, ANTIBODY FRAGMENTS AND SERUM PROTEINS

CHAPTER FIVE

• CONCLUSION
• RECOMMENDATION
• REFERENCES

CHAPTER ONE

   1.0                                            INTRODUCTION

1.1                                  BACKGROUND OF THE STUDY

Alpha particles, also called alpha ray or alpha radiation, consist of two protons and two neutrons bound together into a particle identical to a helium-4 nucleus. They are generally produced in the process of alpha decay, but may also be produced in other ways. Alpha particles are named after the first letter in the Greek alphabet, α. The symbol for the alpha particle is α or α²⁺. Because they are identical to helium nuclei, they are also sometimes written as He²⁺ or ⁴₂He²⁺ indicating a helium ion with a +2 charge (missing its two electrons). If the ion gains electrons from its environment, the alpha particle becomes a normal (electrically neutral) helium atom ⁴
₂He.

Alpha particles, like helium nuclei, have a net spin of zero. Due to the mechanism of their production in standard alpha radioactive decay, alpha particles generally have a kinetic energy of about 5 MeV, and a velocity in the vicinity of 5% the speed of light. (See discussion below for the limits of these figures in alpha decay.) They are a highly ionizing form of particle radiation, and have low penetration depth. They can be stopped by a few centimeters of air, or by the skin.

However, so-called long range alpha particles from ternary fission are three times as energetic, and penetrate three times as far. As noted, the helium nuclei that form 10–12% of cosmic rays are also usually of much higher energy than those produced by nuclear decay processes, and are thus capable of being highly penetrating and able to traverse the human body and also many meters of dense solid shielding, depending on their energy. To a lesser extent, this is also true of very high-energy helium nuclei produced by particle accelerators.

When alpha particle emitting isotopes are ingested, they are far more dangerous than their half-life or decay rate would suggest, due to the high relative biological effectiveness of alpha radiation to cause biological damage. Alpha radiation is an average of about 20 times more dangerous, and in experiments with inhaled alpha emitters, up to 1000 times more dangerous than an equivalent activity of beta emitting or gamma emitting radioisotopes [Krane, Kenneth S. 1988].

The development of new radiotracers for application in personalized medicine with PET has experienced enormous progress over the last decade, which is reflected in the large and still growing number of valuable compounds used for imaging of different diseases. A tendency that can be observed in this PET tracer development is the utilization of labeled targeting vectors that accumulate with high specificity at the target site, allowing for a highly sensitive target visualization. Many of these vectors are relatively large structures exhibiting high molecular weights as well as slow pharmacokinetics, necessitating the use of radionuclides with long half-lives in order to fully exploit the potential of the used targeting vectors for diagnostic imaging [Krane, Kenneth S. 1988].

Interest in ⁸⁹Zr has increased over the last several years as it exhibits a long half-life, making it ideally suited for imaging studies with slowly-accumulating bioactive molecules, allowing for imaging of biological processes at late time-points after tracer application. ⁸⁹Zr—about which excellent other reviews are available [Krane, Kenneth S. 1988]—produces positrons with a probability of 22.3% and a mean energy of 0.389 MeV, which is between the positron energies of ¹⁸F (mean β⁺ energy of 0.250 MeV) and ⁶⁸Ga (mean β⁺ energy of 0.836 MeV), and thus allows for high resolution PET images. ⁸⁹Zr is produced via cyclotron using ⁸⁹Y (which has a natural abundance of 100%) as target material in the ⁸⁹Y(p,n)⁸⁹Zr nuclear reaction [Little John B, 1985] and can be obtained in high isolated yields of 94–99.5% and very high radionuclidic purity of 99.99% [Little John B, 1985].

Although ¹⁸F exhibits very favorable physical decay characteristics of 96.7% positron emission probability and a low positron energy, it cannot be used for in vivo imaging of biomolecules with slow pharmacokinetics due to its rather short half-life of 109 min. Thus, the use of ¹⁸F, as well as that of 68Ga (t_1/2 = 68 min) and ¹¹C (t_1/2 = 20 min) which are the common nuclides in routine PET imaging applications, is restricted to imaging of the biodistribution of smaller radiolabeled bioactive compounds such as peptides and small molecules. As a result, ⁶⁴Cu has attracted attention as it exhibits a longer half-life of 12.7 h together with a main positron energy of 0.653 MeV and low spatial resolution loss of 0.7 mm, allowing for an extended imaging of biological processes. However, ⁸⁹Zr is even more interesting for the radiolabeling of slowly-accumulating radiopharmaceuticals as it exhibits a longer half-life of 3.27 days, being particularly suited for in vivo imaging of antibodies, nanoparticles and other large bioactive molecules [Little John B, 1985]. However, this results in higher absorbed organ doses than in case of ¹⁸F-labeled tracers such as [¹⁸F] FDG [Little John B, 1985]. ¹²⁴I could also serve as a possible alternative for long-term imaging, exhibiting a half-life of 4.18 days, but in comparison to ⁸⁹Zr it exhibits higher main positron energies of 1.54 and 2.14 MeV resulting in a relatively high intrinsic spatial resolution loss of 2.3 mm, whereas ⁸⁹Zr with an intrinsic spatial resolution loss of 1.0 mm gives much better imaging results [Darling David, 2010]. Furthermore, ¹²⁴I is a so-called non-pure positron-emitter, producing in significant amount high-energy photons of different energy (603 keV (63.0%), 1691 keV (10.9%) and 723 keV (10.4%) [Darling David, 2010]) which can result in random and scatter non-true coincidences and thus background noise, whereas ⁸⁹Zr produces mainly one additional γ-line at 909 keV (909 keV (99.9%), 1657 (0.1%), 1713 keV (0.77%) and 1.744 keV (0.13%) [Darling David, 2010]). Thus, the application of ¹²⁴I necessitates the use of appropriate image reconstruction techniques in order to achieve a reasonable image quality [Darling David, 2010].

Although ⁸⁹Zr is mainly used for in vivo PET imaging, its use is not restricted to PET alone, as it can also be used for in vivo Cerenkov luminescence imaging (CLI). This imaging modality is based on luminescence that can be observed when a particle travels faster than light in the examined medium, is fully quantifiable and can be correlated to the respective PET signal [Christensen D. M, 2014]. Thus, Cerenkov luminescence imaging was shown to be applicable in image-guided surgery using ⁸⁹Zr-labeled antibodies [Christensen D. M, 2014]. However, the main application of ⁸⁹Zr is–and probably will remain–in vivo PET imaging of biological processes. Among ⁸⁹Zr-labeled bioactive molecules used for PET imaging, mainly antibodies were labeled with ⁸⁹Zr so far [Christensen D. M, 2014] although its use is not limited to these biomolecules. Beyond antibodies, ⁸⁹Zr-labeling was also shown to be applicable in long-term PET studies of peptides and peptide multimers, nanoparticles, microspheres, targeted nanotubes, liposomes and proteins [Christensen D. M, 2014].

1.2                                         AIM OF THE PROJECT

At the end of this work student involved shall be able learn and prove the reaction of positron emitter with alpha particles. Also, the isotope of zirconium and alpha particles shall also be studied.

1.3                                      SCOPE OF THE PROJECT

In this work, the radiolabeling with ⁸⁹Zr, the synthesis strategies to introduce desferrioxamine B (DFO) into bioactive molecules, the stability of the ⁸⁹Zr-DFO complex and its chemical conjugation as well as an overview of ⁸⁹Zr-labeled biomolecules and their applications will be presented and critically discussed.