Design of Radioprobes for Pet and Spect Imaging

António Paulo

Radiopharmaceutical Sciences Group, IST/CTN, Instituto Superior Técnico, Universidade Técnica de Lisboa,

Estrada Nacional 10, km 139,7,2695-066 Bobadela LRS, Portugal

Keywords: Radiopharmaceuticals, Nuclear Cardiology, PET, SPECT.

Abstract: Nuclear Cardiology is an important and non-invasive tool for the clinical evaluation of patients with known

or suspected coronary artery disease (CAD), one of the leading causes of death in western countries. The

advancement of this field depends on the continuous improvement and development of equipment and

signal processing technologies. However, its success is primarily determined by the design and development

of new radiopharmaceuticals suitable for Single Photon Emission Computed Tomography (SPECT) and

Positron Emission Tomography (PET) imaging. Nuclear cardiology started in the mid-1970s with the use of

201

Tl-thallous chloride, which has been the firstly approved radiopharmaceutical for perfusion cardiac

imaging. Later on,

99m

Tc-Sestamibi was introduced and approved for clinical use. Nowadays,

99m

Tc-

Sestamibi is the most used radioprobe for SPECT cardiac imaging. In the case of PET, nuclear cardiology

still relies mainly on the use of [

F]-2-fluoro-2-deoxy-glucose, which is the gold standard metabolic tracer

for cardiac imaging. Until now, a variety of other SPECT and PET radioprobes have been tested as

radiopharmaceuticals for cardiac imaging. This contribution reviews representative examples of the

chemical/radiochemical strategies that have been used to design perfusion and target-specific

radiopharmaceuticals for cardiac imaging.

1 INTRODUCTION

Nuclear Medicine uses radioactive compounds for in

vivo imaging and therapeutic purposes. Such

compounds, named radiopharmaceuticals, are used

in very low concentration (10

-8

- 10

-12

M), having no

pharmacological effect.

For in vivo imaging there are two nuclear

modalities: Single Photon Emission Computed

Tomography (SPECT) and Positron Emission

Tomography (PET), which use  or β

emitting

radionuclides, respectively (Table 1) (Correia,

2011); (Morais, 2012a); (Morais 2012b). In the case

of SPECT, the radionuclides decay by electron

capture (EC) or isomeric transition (IT) with

emission of penetrating photons having energies in

the range 100-250 KeV. In PET, the 

particles

emitted by the radionuclide react with the electrons

from the medium releasing two photons of 511 KeV,

as a result of annihilation reactions. In both cases,

the resulting photons (100-250 KeV or 511 KeV) are

efficiently detected outside the body leading to

clinically useful medical images.

Table 1: Examples of radionuclides for medical imaging.

Nuclide Physical half-life Mode of decay (%) Application

99m

6.0 h IT (100) SPECT

123

13.2 h EC (100) SPECT

1.83 h



(97)

EC (3)

PET

20.3 min



(100)

PET

14.7 h



(33)

EC (66)

PET

111

2.80 d EC (100) SPECT

3.26 d EC (100) SPECT

1.13 h



(99)

EC (10)

PET

9.67 min



(98)

EC (2)

PET

12.7 h



(40),



(19)

EC (41)

PET

117m

13.6 d IT (100) PET

Perfusion versus Target-specific Radiopharma-

ceuticals. The biodistribution of radiopharmaceu-

ticals can be determined by their chemical and

physical properties – perfusion radiopharma-

ceuticals - or by their biological interactions -

Paulo A..

Design of Radioprobes for Pet and Spect Imaging.

DOI: 10.5220/0004663400750078

In Proceedings of the International Congress on Cardiovascular Technologies (VisualCardio-2013), pages 75-78

ISBN: 978-989-8565-78-5

 2013 SCITEPRESS (Science and Technology Publications, Lda.)

target-specific radiopharmaceuticals (Fig. 1). The

biological distribution of perfusion agents is

determined by blood flow and these agents target

high capacity systems, such as phagocytosis,

hepatocyte clearance, glomerular filtration. The

target-specific radiopharmaceuticals target low

capacity systems, and their biodistribution is

determined by specific protein interactions, for

example antigen, enzymatic or receptor-binding

interactions (Correia, 2011); (Morais, 2012a);

(Morais 2012b).

Figure 1: Schematic representation of perfusion and

target-specific radiopharmaceuticals.

In this contribution, we review representative

examples of the chemical/radiochemical strategies

that have been used to design perfusion and target-

specific radiopharmaceuticals for cardiac imaging.

This will comprise compounds labelled with

99m

F but also radioprobes containing less common

radionuclides like

123

Cu or

117m

Sn.

2 RADIOPHARMACEUTICALS

FOR CARDIAC IMAGING

Nuclear Cardiology is an important and non-

invasive tool for the clinical evaluation of patients

with known or suspected coronary artery disease

(CAD), one of the leading causes of death in western

countries (Notghi, 2011); (Osborn, 2012). The

clinical importance of nuclear cardiology stems from

the unique advantages of Nuclear Imaging

Modalities (SPECT and PET), such as their high

intrinsic sensitivity, non–invasiveness and

specificity. The advances on nuclear cardiology

depend on the continuous improvement and

development of instrumentation and signal

processing technologies. However, its success is

primarily determined by the design, development

and validation of new, more sensitive and specific

radiopharmaceuticals.

2.1 SPECT Radioprobes

Nuclear cardiology started in the mid-1970s with the

use of

201

Tl-thallous chloride, which has been the

firstly approved radiopharmaceutical for perfusion

cardiac imaging by SPECT.

99m

Tc is the most widely

used SPECT radionuclide, due to its ideal nuclear

properties, low-cost and availability from

commercial

Mo/

99m

Tc generators. Later on, an

alternative

99m

Tc-based cardiac perfusion agent -

99m

Tc-Sestamibi (Fig. 2) – was introduced for

SPECT cardiac imaging, overcoming the limitations

associated with the unfavourable decay properties of

201

Tl (Maria, 2009).

99m

Tc-Sestamibi corresponds to

an organometallic Tc(I) compound, which is

synthesized in aqueous solution starting from the

Tc(VII) permetallate anion (

99m

TcO

) that is

reduced prior to its complexation by the isonitrile

ligands (Wackers, 1989).

Figure 2: Selected examples of SPECT radioprobes for

cardiac imaging.

Other radiometals, like

Ga,

111

In or the less

common

117m

Sn (see Table 1), are also relevant for

SPECT imaging. For instance, it has been recently

reported that the target-specific agent

117m

Sn-DOTA-

Annexin (TA) has potential for in vivo imaging of

vulnerable plaque (Strauss, 2013). This agent

corresponds to a Sn(II) complex with a macrocyclic

DOTA ligand functionalized with Annexin-V for the

targeting of phosphatidylserine (PS) that is

externalized in cells undergoing apoptosis.

Interestingly,

117m

Sn is a very promising

radionuclide for the development of theranostic

radiopharmaceuticals, as it decays via isomeric

transition with the emission of monoenergetic

conversion electrons. The pre-clinical evaluation of

117m

Sn-DOTA-Annexin in ApoE-/- mouse has

shown that this radioconjugate has some therapeutic

potential for the stabilization of vulnerable plaques

(Strauss, 2013).

Besides metal-based compounds, several

examples of radioiodinated molecules, such as

123

I-

BMIPP and

123

I-MIBG (Fig. 2), have also shown

promising for SPECT cardiac imaging. The methyl-

CARDIOTECHNIX2013-InternationalCongressonCardiovascularTechnologies

p-[

123

I]-iodophenyl-pentadecanoic acid (BMIPP) is a

radiolabeled branched fatty acid with the ability to

assess in vivo the viability of cardiac tissue, playing

an important role for identifying ischemia (Kontos,

2010). The meta-[

123

I]-iodobenzylguanidine (MIBG)

is a norepinephrine analogue that allow the in vivo

imaging of cardiac innervation, being useful to

assess the severity of heart failure and prognosis

(Tamaki, 2011).

123

I-BMIPP and

123

I-MIBG can be

obtained by isotopic exchange of stable

127

I by

123

I in

BMIPP and MIBG, respectively, using Cu(II) salts

as catalyst in the presence of a reducing agent. High

specific activity

123

I-MIBG is achievable by

electrophilic radioiodination of adequate stannylated

precursors (Vallabhajosula, 2011).

F‐FDG

F‐Flurpiridaz

62/64

Cu‐PTSM

Figure 3: Selected examples of PET radioprobes for

cardiac imaging.

2.2 PET Radioprobes

Until recently, the cyclotron-produced carbon-11

(

C) and fluorine-18 (

F) (Table 1) were the most

explored PET radionuclides on the design of

molecular imaging agents. Usually, labelling with

C frequently involves introduction of a [

C]methyl

group in the biomolecule via selective N- and O-

methylation (Ametamey, 2008). However, the very

short-life of this radionuclide (T

1/2

= 20.4 min) limits

its use to on-site cyclotron facilities, and requires

rapid one-step radiosynthesis. The longer

half-life of

F (T

1/2

= 110 min) allows for multistep

radiosynthesis, longer in vivo investigation and

commercial distribution to other clinical PET

centers. Radiofluorination reactions can be achieved

with either electrophilic or nucleophilic radioactive

fluoride. However, reactions with the less reactive

nucleophilic radiofluoride are more selective and

provide

F-labeled compounds in higher yields and

higher specific activity (Ametamey, 2008). For all

these reasons,

F remains the most used PET

radionuclide in radiopharmaceutical research.

In the particular case of nuclear cardiology PET

imaging relies mainly on the use of [

F]-2-fluoro-2-

deoxy-glucose, which has emerged several years ago

as the gold standard metabolic tracer for cardiac

imaging. (Strauss et al., 2013) Nowadays,

F-FDG

is produced worldwide in a large number of PET

facilities and under GMP conditions, based on a

nucleophilic reaction between a mannose triflate

precursor and [

F]fluoride.

More recently,

F-flurpiridaz (Fig. 2) a

structural analog of pyridaben obtained by

radiofluorination of a toluenesulfonate ester

precursor, started to be clinically evaluated as a PET

tracer for myocardial perfusion imaging.

F-

flurpiridaz targets the mitochondrial complex I (MC-

1), a mitochondrial protein found primarily in

myocardial cells, presenting a rapid uptake and slow

washout in cardiomyocytes. These characteristics

allow for a fast and sustained accumulation in the

heart (Ya, 2011).

There are several positron emitter radiometals

that are relevant the design of PET probes for

cardiac imaging, as is the case of

Ga and

62/64

(Table 1) (Cutler, 2013).

Ga is a positron emitter

readily accessible from the

Ge/

Ga generator,

offering the possibility to obtain on site a PET

radionuclide without needing the presence of a

nearby cyclotron. This possibility might open the

way to an important role for

Ga in PET imaging,

similarly to the role played by

99m

Tc in SPECT

imaging during the past few decades. Recently,

several cationic and lipophilic Ga(III) complexes

with hexadentate ligands have been synthesized and

pre-clinically evaluated as radioactive probes for

myocardial perfusion imaging (Hsiao, 2009).

Despite some encouraging results, none of the

reported Ga(III) complexes has shown potential to

be clinically evaluated as a PET probe for cardiac

imaging. So far,

62/64

Cu –PTSM has been the unique

metal-based compound that showed promising

biological properties as a PET perfusion imaging

agent. Although the mechanism is not fully

understood, it is considered that this small-sized,

neutral and lipophilic Cu(II) complex is retained in

the cells due to its intracellular reduction to Cu(I),

followed by release of the bis(thiosemicarbazone)

ligand (H

PTSM) (Paterson, 2011).

In summary, the chemical and structural

diversity of PET and SPECT radioprobes allowed

the design of several perfusion, metabolic and

target-specific agents for cardiac imaging, some of

them already in clinical use and others undergoing

clinical evaluation. Despite this success, there is still

room to investigate new radioprobes for nuclear

DesignofRadioprobesforPetandSpectImaging

cardiology, aiming at their translation from the

bench to the patient bedside.

REFERENCES

Ametamey, S. M., Honer, M., Schubiger, P. A.: Molecular

imaging with PET, Chem. Rev. 108 (2008) 1501-

1516.

Correia, J. D. G., Paulo, A., Raposinho, P. D., Santos, I.:

Radiometallated peptides for molecular imaging and

targeted therapy Dalton Trans 40 (2011) 6144-6167.

Cutler, C. S., Hennkens ,H. M., Sisay, N., Huclier-Markai,

S., Jurisson, S. S.: Radiometals for Combined Imaging

and Therapy, Chem. Rev. 113 (2013) 858-883.

Hsiao,Y-M., Mathias, C. J., Wey, S-P., Fanwick, P. E.,

Green, M. A.: Synthesis and biodistribution of

lipophilic and monocationic gallium radiopharma-

ceuticals derived from N,N′-bis(3-aminopropyl)-N,N′-

dimethylethylenediamine: potential agents for PET

myocardial imaging with

Ga, Nucl. Med. Biol., 36

(2009) 39-45.

Kontos, M. C., Dilsizian,V., Weiland, F., DePuey, G.,

Mahmarian, J. J., Iskandrian, A. E., Bateman, T. M.,

Heller, G. V., Ananthasubramaniam, K., Li, Y.,

Goldman, J. L., Armor, T., Kacena, K. A., LaFrance,

N. D., Garcia, E. V., Babich, J. W., Udelson, J. E.:

Iodofiltic Acid I 123 (BMIPP) Fatty Acid Imaging

Improves Initial Diagnosis in Emergency

DepartmentPatients With Suspected Acute Coronary

Syndromes, J. Am. Coll. Card. 56 (2010) 290-299.

Maria, L., Fernandes ,C., Garcia, R,. Gano, L., Paulo, A.,

Santos, I. C., Santos, I.: Tris(pyrazolyl)methane

99m

tricarbonyl complexes for myocardial imaging, Dalton

Trans (2009) 603–606.

Morais, G. R., Paulo, A., Santos, I.: Organometallic

Complexes for SPECT Imaging and/or Radionuclide

Therapy, Organometallics 31 (2012a) 5693-5714.

Morais, G. R., Paulo, A., Santos, I.: Synthetic Overview of

Radiolabeled Compounds for β-Amyloid Targeting,

Eur. J. Org. Chem. (2012b) 1279-1293.

Notghi, A., Low, C. S.: Myocardial perfusion

scintigraphy: past, present and future, Brit. J. Radiol.

84 (2011) S229–S236.

Osborn, E. A., Jaffer, F. A.: The Year in Molecular

Imaging, J. Am. Coll. Card. 58 (2012) 317-328.

Paterson, B. M., Donnelly, P. S.: Copper complexes of

bis(thiosemicarbazones): From chemotherapeutics to

diagnostic and therapeutic radiopharmaceuticals.

Chem. Soc. Rev. 40 (2011) 3005–3018.

Strauss, H. W., Narula, J., Orellana, P., Jaimovich, R.,

Stevenson, N., Gonzales, G., Srivastava, S.: Targeting

of vulnerable plaque using [tin-117m]-DOTA-

annexin, J Nucl Med. 54 (Supplement 2) (2013) 1667.

Tamaki, N.; Yoshinaga, K.: Novel iodinated tracers,

MIBG and BMIPP, for nuclear cardiology, J. Nucl.

Cardiol. 18 (2011) 135-143.

Vallabhajosula, S., Nikolopoulou, A.: Radioiodinated

Metaiodobenzylguanidine (MIBG): Radiochemistry,

Biology, and Pharmacology, Semin. Nucl. Med. 41

(2011) 324-33.

Wackers, F. J. T., Berman, D. S., Maddahi, J., Watson, D.

D., Beller, G. A., Strauss, H. W., Boucher, C. A.,

Picard, M., Holman, B. L., Fridrich, ,R., Inglese, E.,

Delaloye, B., Bischofdelaloye, A., Camin, L.,

Mckusick K.: Technetium-99m Hexakis 2-

Methoxyisobutyl Isonitrile: Human Biodistribution,

Dosimetry, Safety, and Preliminary Comparison to

Thallium-201 for Myocardial Perfusion Imaging. J

Nucl Med 30 (1989) 301-311.

Yu, M., Nekolla, S. G., Schwaiger, M., Robinson, S. P.:

The next generation of cardiac positron emission

tomography imaging agents: Discovery of Flurpiridaz

F-18 for detection of coronary disease, Semin. Nucl.

Med. 41 (2011) 305-313.

CARDIOTECHNIX2013-InternationalCongressonCardiovascularTechnologies