Developing new molecular imaging probes for PET

doi:10.1016/j.ymeth.2009.03.010

Methods

Volume 48, Issue 2, June 2009, Pages 104-111

https://doi.org/10.1016/j.ymeth.2009.03.010 Get rights and content

Abstract

Positron emission tomography (PET) is a fully translational molecular imaging technique that requires specific probes radiolabelled with short-lived positron emitting radionuclides. This review discusses relevant methods which are applied throughout the different steps in the development of new PET probes for in vivo visualization of specific molecular targets related to diagnosis or important for drug development.

Introduction

Molecular imaging is a quickly developing research area that allows non-invasive visualization of molecular processes in vivo. Positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabelled with a usually short-lived positron emitting radionuclide which can be quantified in vivo by detection of the gamma rays formed as a result of annihilation of the positrons emitted. Development of new imaging probes for PET requires a multidisciplinary approach consisting of target selection, organic synthesis, radiolabelling, in vitro and in vivo evaluation and kinetic modeling of the radiolabelled compound before it can be applied in preclinical or clinical research. Several techniques and methods are required in each of the different steps of the challenging path of the development of an imaging probe from bench to bedside.

Section snippets

Target selection

As positron emission tomography is not restricted to medical diagnostic purposes but is increasingly used in drug development [1], [2], [3] the target for which a new PET radiopharmaceutical is developed may be (a) a pathological up- or downregulation of the expression of a biomolecule associated with a certain pathology to be diagnosed including biomolecules expressed as gene reporters or cell tracking probes [4], (b) the same target for which new drugs are in development, or (c) a surrogate

Lead selection

Once the target has been identified, ligands for the target need to be selected, either by rational design based on structural biology [11] or by high throughput screening of libraries of compounds, or by a combination of both. In the latter case generally libraries are selected based on rational design to speed up the process by limiting the number of compounds to be screened [12].

Lead optimization

The hits identified by the former technique can be derivatized to identify molecular regions which are critical

Choice and production of radionuclide for radiolabelling

The choice of the radionuclide is imposed by its physical and chemical characteristics and its availability. Table 1 lists the most frequently used positron emitting radionuclides with some of their physical characteristics. The positron energy and its resulting range in water are inversely correlated with the PET image resolution obtained, especially when using high resolution μPET for small animal imaging. Radionuclides such as ⁶⁸Ga and ¹²⁴I with relatively large positron ranges will thus

In vitro tests

Depending on the probe development strategy, in vitro tests may already have been performed on the non-radioactive reference compounds to select the optimal molecules to be radiolabelled.

In vitro tests such as determination of protein binding and stability in plasma can however also be performed on the radiolabelled molecules. Binding competition studies with cells expressing the target receptor allow to assess the affinity of the radiolabelled compound but also to evaluate internalization [7],

In vivo/ex vivo evaluation in laboratory animals

Biodistribution studies in mice or rats allow evaluation of the pharmacokinetics of the PET tracer. The percentage of injected activity in different organs and tissues at several time points post-injection can be determined by sacrificing the animal after intravenous injection followed by dissection, weighing of the organs and counting of the activity in the different body parts using a gamma counter. The latter studies require limited activities (10–1000 kBq) of the tracer to be injected and

Clinical trial application

In Europe, a clinical trial application (CTA) needs to be submitted to the national health authorities and local ethical committee prior to the use of PET imaging probes in humans [81]. Such an application must include information on any safety risk, based on results of a toxicity study and radiation dose estimation. In view of the very low mass amounts of the new radiotracer which are administered to volunteers and/or patients, the toxicity study can be limited to a single dose toxicity study

Concluding remarks

The development of new molecular probes for PET is a challenging research area with a rapid growth parallel to the growth of the number of PET sites worldwide. The availability of new molecular probes for specific molecular targets is beneficial for basic research, drug development and validation and for clinical diagnosis and therapy follow up.

In addition to specific PET probe development in academic PET research centres, the interest of several major players within pharmaceutical industry

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Review ArticleDeveloping new molecular imaging probes for PET

Abstract

Introduction

Section snippets

Target selection

Lead selection

Lead optimization

Choice and production of radionuclide for radiolabelling

In vitro tests

In vivo/ex vivo evaluation in laboratory animals

Clinical trial application

Concluding remarks

Drug Discov. Today

Methods

Nucl. Med. Biol.

Bioorg. Med. Chem.

Nucl. Med. Biol.

Appl. Radiat. Isot.

Contemp. Clin. Trials

Nucl. Med. Biol.

Nucl. Med. Biol.

Nucl. Med. Biol.

Appl. Radiat. Isot.

Nucl. Med. Biol.

Nucl. Med. Biol.

J. Chromatogr. A

Appl. Radiat. Isot.

Mol. Imaging Biol.

Nucl. Med. Biol.

Nucl. Med. Biol.

Neurosci. Lett.

Neurobiol. Aging

Nucl. Med. Biol.

Neuroimage

Neuroimage

Nucl. Med. Biol.

Clin. Pharmacol. Ther.

Neuropsychopharmacology

Handb. Exp. Pharmacol.

Handb. Exp. Pharmacol.

Synapse

J. Nucl. Med.

J. Cereb. Blood Flow Metab.

Curr. Opin. Drug Discov. Dev.

Comb. Chem. High Throughput Screen.

Q. J. Nucl. Med. Mol. Imaging

Curr. Drug Metab.

Curr. Opin. Drug Discov. Dev.

Synapse

Eur. J. Nucl. Med. Mol. Imaging

Curr. Med. Chem.

Ernst Schering Res. Found Workshop

Angew. Chem. Int. Ed. Engl.

Nuklearmedizin

Review Article
Developing new molecular imaging probes for PET