Journal of Nuclear and Radiochemical Sciences, Vol. 6, No. 3, pp. 177-181, 2005

Recent Advances in 99mTc Radiopharmaceuticals
Yasushi Arano*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku,
Chiba 260-8675, Japan
Received: July 31, 2005; In Final Form: September 30, 2005
When 99mTc was first applied to radiopharmaceuticals for diagnostic nuclear medicine, major efforts were focusedon the development of 99mTc complexes for excretory organs such as the liver and kidney. Over the past 30 years, asignificant advance was made in technetium chemistry and radiopharmaceutical design. Now, 99mTc radiopharmaceuticals for measuring regional cerebral and myocardial blood flow are available in clinical studies. Morerecently, transporter functions of the brain can also be visualized with 99mTc radiopharmaceuticals. In this manuscript, recent advances in 99mTc radiopharmaceuticals will be briefly reviewed.

for brain and myocardial functions. In this paper, progress indeveloping 99mTc radiopharmaceuticals will be briefly reviewed.

1. Introduction
Technetium-99m (99mTc) is one of the most desirable radionuclides in diagnostic nuclear medicine, due to an emission ofa gamma ray of optimal energy (140 keV), a suitable half-life(6 h), and availability from 99Mo-99mTc generator systems. In
addition, development of 99mTc radiopharmaceuticals for tumor
imaging paves the way for therapeutic radiopharmaceuticals
with high energy beta emitters 186Re and 188Re since chemical
properties of Tc are close to those of Re.
Technetium (Z = 43) is situated in the middle of the secondrow transition series and does not have stable isotopes, which
retarded the development of its chemistry. At the initial stageof 99mTc radiopharmaceutical development, major efforts werefocused on imaging excretory organs such as the liver and kidney, since it was thought that Tc is a foreign substance andshould be recognized as such by the body. In 1982, Yokoyama
et al. reported that a 99mTc complex of glucosone bis (thiosemicarbazone) (Figure 1A) showed an uptake into normal brain inlaboratory animals.1, 2 They also reported that 99mTc-dithiosemicarbazone complexes appended with a tertiary or a quarternary amine group showed myocardial uptake.1, 3 Meanwhile,the Davison and Jones group demonstrated that pentavalent oxotechnetium (5+) forms a five-coordinated mononuclear complex
of high stability with a N2S2 ligand (Figure 1B).4 These findings
encouraged further efforts to develop 99mTc radiopharmaceuticals

(A)
N
HC N

(B)
NH2
O

S

Tc

C N X
HO CH N
HC OH
HC OH
CH2OH

S

O

N
S

O
Tc

O

N
S

NH2
X: OH, Cl

99m

Figure 1.
Tc complexes that paved the way for currently available
99m
Tc radiopharmaceuticals. (A) 99mTc-dithiosemicarbazone derivative of glucose, (B) oxo99mTc(V) complex containing a 99mTcON2S2 core.
*Corresponding author. E-mail: arano@p.cbiba-u.ac.jp. FAX:
+81-43-226-2897.

2. 99mTc Radiopharmaceuticals for Perfusion Imaging
2.1. Regional cerebral blood flow. To determine regional
cerebral blood flow, coordination molecules (ligands) arerequested to provide 99mTc complexes that can penetrate theintact blood-brain barrier (BBB) in response to the blood flow.
A variety of ligands were developed that form mononuclear,neutral, lipophilic and stable 99mTc complexes. These include
diaminodithiolate (DADT or BAT), 5 bis(thiosemicarbazone)
derivatives (DTS),6 propylene amine oxime (PnAO),7 as illustrated in Figure 2. Although all 99mTc complexes penetrated theintact BBB with significant initial brain uptake, they were also
marked by rapid washout from the brain, due to a lack of an
appropriate functional group that fixed the 99mTc complexes inthe brain. Since radioiodinated compounds with amine derivatives such as [123I]N-isopropyliodoamphetamine ([123I]IMP) and[123I]N,N,N’-trimethyl-N’-(2-hydroxy-3-methyl-5-iodobenzyl)1,3-propane diamine ([123I]HIPDM) 8 demonstrated significant
brain uptake and retention sufficient for external imaging, initialefforts were made to append an amine group to the neutral andlipophilic mononuclear 99mTc complexes. Although this chemical modification provided 99mTc complexes of longer residence
time in the brain (e.g. an N-piperidinylethyl derivative of 99mTcDADT), this resulted in the formation of two 99mTc complexes
with different biological characteristics,9 which were identified
as syn and anti isomers. This hampered further efforts to develop
cerebral perfusion agents based on this molecular design.
In 1984, Fair et al. synthesized and characterized a technetium complex of PnAO as a neutral complex with a square pyramidal structure.10 Volkert et al. found that 99mTc-PnAO passively
penetrated the intact blood-brain-barrier in laboratory animals
with a first-pass efficiency of 80%, followed by rapid washout
(A)

(B)

(C)

NH HN

NH HN

S H HS

N

N

OH

OH

N
H3CHN

N

N

SH HS

N

NHCH3

Figure 2. Presentative N2S2 ligands that provide neutral, lipophilicand stable mononuclear 99mTc complexes that cross the intact bloodbrain barrier. (A) diaminodithiolate (DADT or BAT), (B) propylene
amine oxime (PnAO), and (C) pentane-2,4-dione bis(thiosemicarbazone).

© 2005 The Japan Society of Nuclear and Radiochemical Sciences
Published on Web 12/28/2005

178 J. Nucl. Radiochem. Sci., Vol. 6, No. 3, 2005

Arano

7

from the brain. Following a series of structure-distribution
studies of 99mTc complexes of PnAO derivatives, Neirinckx et al.
selected d,l-diastereoisomer of hexamethyl propyleneamine
oxime (HM-PAO) (Figure 3A).11 99mTc-HM-PAO showed rapid
uptake in the brain, followed by high residence times of radioactivity in the brain up to 24 h post-injection, due to rapid conversion of lipophilic 99mTc-HM-PAO to more hydrophilic secondary
complexes. Further studies showed that intracerebral glutathione (GSH) would be involved in the conversion of 99mTc-HMPAO to hydrophilic forms, which would account for the retentionof this 99mTc complex in brain and other cells.12
Meanwhile, Walovitch et al. reported that 99mTc complex of
N,N’-1,2-ethanediylbis-L-cysteine diethylester (ECD) (Figure3B) exhibited high uptake and retention of baboon brain.13
Metabolic studies suggested that the brain retention of 99mTcECD would be caused by rapid metabolism to a polar monoester-monoacid metabolite that is trapped in the brain. Althoughhigh initial brain uptake was observed with 99mTc-D,D-ECD isomer, rapid elimination from the brain was observed, suggesting
enzyme-mediated hydrolysis of the ester in 99mTc-ECD.
Clinical studies showed that 99mTc-ECD provided diagnostic
information comparable to that obtained by PET brain perfusion agent.
2.2. Myocardial Perfusion Agents. In a search for 99mTc
radiopharmaceuticals that provide diagnostic information compatible to those of 201Tl, efforts were made to synthesize cationic 99mTc complexes with appropriate lipophilicity so that thecomplexes can reflect myocardial blood flow. The first cationic 99mTc chelate that exhibited significant myocardial uptake
in animals was 99mTc complexes of trans-[99mTc(DIARS) 2X2]+,
where DIARS represents the o-phenylenebis(dimethylarsine)
ligand and X represents chloride or bromide,14 as shown in
Figure 4A. To reduce lipophilicity of the complex and replace
harmful arsine to another atom, they utilized 1,2-bis(dimethylphosphino)ethane (DMPE) as a ligand for a 99mTc (III) cationiccomplex, trans-[99mTc(DMPE) 2Cl2] + (Figure 4B).15 This cationic complex, however, was reduced to neutral 99mTc(II) form,
(A)

(B)

C2 H5OOC

O N

N

Tc
N
O

N O NH
Tc
S

N

COOC2 H5SO

H

Figure 3. Clinically applied 99mTc radiopharmaceuticals for brain
perfusion. (A) 99mTc-L,L-ECD and (B) 99mTc-HM-PAO.
(A)

(B)

Cl

Cl
As

As

As

P

P

P
TcIII

III

Tc

(C)

As

P

P

P

P
TcI

P

P
P

Cl

Cl

(D)

(E)

(F)

CN-R

O

OEt OEt O OEt OEt

R-NC

TcI

CN-R

P

P

V

CN-R

P
O

A large number of organic compounds labeled with 11C, 18F
and 123I have been designed and synthesized as radiopharmaceuticals for imaging of receptors, transporters and enzymes
activites. Owing to the progress in technetium chemistry, recent
efforts have been directed toward the development of 99mTc
radiopharmaceuticals for targeted imaging.
To develop 99mTc compounds for targeted imaging, a stable
and neutral 99mTc chelate was conjugated to a compound thatpossesses a specific localization mechanism to target tissues(e.g. receptors, transporters and enzymes). This approach isanalogous to the strategy employed for proteins and peptide
labeling with 99mTc. When the chemical design is further applied
to small molecular weight compounds, strategic replacement of99m
Tc chelating moiety at sterically tolerant sites of mother molecules plays a critical role in order to minimize the loss of theoriginal bioactivity. 99mTc complexes for dopamine transporter
imaging, simultaneously reported by two research groups, constitute representative 99mTc compounds based on the chemical
design.21, 22 Each compound possesses a 99mTc complex of N2S2
ligand at a different position in tropane moiety (Technephine:
Figure 5B and TRODAT-1; Figure 5C). Despite the structuraldifferences, both compounds crossed the intact BBB and boundto the dopamine pre-synaptic transporter. Specific uptake of
TRODAT-1 in dopamine transporter located in the basal ganglia
was demonstrated in human studies.22, 23 These studies suggested that further studies on structure-distribution and struct u r e - a c t i v i t y r e l a t i o n s i p w o u l d p r o v i d e 9 9 m Tc
radiopharmaceuticals that target receptors or transporters in

P

P

(A)
P

OEt OEt O OEt OEt

R: methoxyisobutyl
99m

3. 99mTc Radiopharmaceuticals for Targeted Imaging

Tc

P

0 16

[ Tc(II)(DMPE) 2Cl2] , which facilitated elimination of thecomplex from myocardium.
During these studies, it was also found that besides the
99m
Tc(III) complex, DMPE also formed [99mTc(I)(DMPE) 3] +(Figure 4C) and [99mTc(V)O2(DMPE)2]+ (Figure 4E) complexes.17
This stimulated further efforts to develop 99mTc cationic complexes for myocardial blood flow. Kelly et al. synthesized cationic and lipophilic 99mTc complex of diphosphine ligand,
1,2-bis[bis(2-ethoxyethylene)phosphino]ethane (tetrofosmin)with a 99mTcO2 core as shown in Figure 4F.18 This complex is
now approved as a radiopharmaceutical for myocardial bloodflow.
Another type of cationic 99mTc complex was developed by Joneset al. who prepared organometallic 99mTc(I) hexakis(isonitrile)
complexes.19 The Tc(I) oxidation state is particularly advantageous because of the kinetic inertness inherent in its low-spin
d6 configuration. After extensive structure-distribution studiesof the isonitrile derivatives, hexakis(2-methoxy-isobutylisonitrile; MIBI) technetium(I) shown in Figure 4D was found to
improve the biodistribution properties when compared with theprototype compound, hexakis(t-butylisonitrile) technetium(I),due to rapid clearance of radioactivity from the liver and lung.
This could be attributed to the metabolism of the ether groups
in MIBI ligand to hydrophilic hydroxyl groups. Further studies
showed that the fundamental myocellular uptake mechanism of
99m
Tc-MIBI involves passive distribution across plasma andmitochondrial membranes and that at equilibrium 99mTc-MIBI
is sequestered within mitochondria by the large negative transmembrane potentials.20

V

Tc

CN-R

R-NC

P

99m

Figure 4.
Tc cationic complexes for measuring myocardial perfusion. (A) [99mTc(III)(DIARS) 2Cl 2] +, (B) [99mTc(III)(DIMPE) 2Cl 2] +,(C) [99mTc(I)(DMPE)3]+, (D) [99mTc(I)MIBI]+, (E) [99mTc(V)O2(DMPE)2]+and (F) [99mTcO2 (tetrofosmin)]+.

(C)

(B)
O

H3 C

N

COOCH3

N

O

H3C

N

Tc
S

S

N

S O S
N
N

COOCH3F

Tc

N
Cl

Figure 5. Chemical structures of (A) tropane, (B) technephine, and(C) TRODAT-I.

J. Nucl. Radiochem. Sci., Vol. 6, No. 3, 2005 179

Recent Advances in 99mTc Radiopharmaceuticals

(A)

O

N

COOH
O

N

Tc
S

(CH2)n-COOH

OC
S

Tc
CO

4. 99mTc Polynuclear Complexes of Bisphosphonates
Although developed in 1970’s, 99mTc complexes of bisphosphonate (diphosphonate, abbreviated as BP) are still mostwidely used radiopharmaceuticals in clinical studies. They
accumulate in bone, especially at sites of high calcium turnoverin actively growing or cancerous bone with easily accessible
unsaturated coordination sphere of Ca2+ in the basic bone structure hydroxyapatite, which render the radiopharmaceuticals useful for visualizing various skeletal cancers.35 High and selective
accumulation of 99mTc BP to cancerous bone promotes palliative
treatment of bone metastases with 186/188Re complexes of BP.36
Despite widespread applications, both 99m Tc complexes of
MDP and HMDP are subject to a time lag of more than 2 h beforebone scanning can be performed after administration, due to theslow elimination rates of radioactivity from systemic circulationand soft tissues. In addition, while a variety of non-radioactive
BPs have found widespread application in clinical managementof a variety of bone disorders such as bone metastases, osteoporosis, and Paget’s disease, there are conflicting results as towhether previous non-radioactive BP treatment for metastaticbone disease would give rise to false-negative bone scintigraphies. To elucidate factors affecting the pharmacokinetics of
186
Re-labeled 1,1-hydroxyethylidenediphosphonate (186ReHEDP), chemical and biological properties of 186Re-HEDP werecompared with those of chemically stable tricarbonyl [186Re](cyclopentadienylcarbonyl amino)-acetic acid] rhenium-conjugated 3-amino-1-hydroxypropylidene-1,1-bisphosphonate([186Re]CpTR-Gly-APD; Figure 7E). The effect of HEDP preor co-administration on the biodistribution of the two 186Re-labeled
compounds was also compared in mice. [186Re]CpTR-Gly-APD
exhibited higher plasma stability, lower plasma protein binding,and higher HA binding than did 186Re-HEDP. In biodistribution
studies, [186Re]CpTR-Gly-APD registered significantly higher
radioactivity levels in bone and faster clearance of radioactivity
from blood than did 186Re-HEDP. However, a significant decreasein bone accumulation was observed when [186Re]CpTR-Gly-APD
was co-injected with HEDP equivalent for that in 186Re-HEDP. In
contrast, no significant difference in bone accumulation wasobserved when [186Re]CpTR-Gly-APD was injected in mice after
5 min injection of a higher amount of HEDP. Similar results wereobserved with 186Re-HEDP in HEDP-pretreated mice. However,

(A)

(B)

OH OH
O P O P O
OH OH

OHH OHO P C P OOHH OHCO

Figure 6. (A) 99mTc-MAMA-based medium (n = 6) and long chain (n= 10) fatty acids, and (B) cyclopentadienyltricarbonyl derivative of
medium chain fatty acid analog, [99mTc]CpTTOA.

(C)

(D)

P O
OH C H3OH

OH OH OHO P C P O
OH H OH(E)OOOH OH OH(B)

O

was excreted from the body as its intact form and its glycine
conjugate, suggesting that [188Re]CpTR-COOH would be partially recognized as an aromatic acid and was metabolized assuch by the body. On the other hand, [188Re]CpTR-Gly was
excreted in the urine as its intact structure. From these studies,
CpTR-Gly would constitute potential alternative for meta-iodohippuric acid in preparing 186/188Re-labled reagents of low
molecular weight polypeptides.34

N
H

O P C

OC

Re
CO

CO

N
H

the brain or other tissues of interest. Recent development oforganometallic technetium and rhenium complexes will also
provide another design for 99mTc radiopharmaceuticals.
External imaging of energy production activity of living cellswith 99mTc compounds constitutes another challenging task.
Based on the studies of 11C- and 123I-labeled medium chain fatty
acid analogs, our efforts were focused on developing medium
chain fatty acid analogs that reflect β-oxidation activity in theliver. Monoamine-monoamide (MAMA) ligand was attached tothe ω-position of hexanoic acid (HA), as shown in Figure 6A.
In biodistribution studies, 99mTc-MAMA-HA showed high initialhepatic uptake, followed by rapid excretion of radioactivity intourine. Analyses of urine revealed 99mTc-MAMA-butylic acid
(BA) as the major radiometabolite. 99mTc-MAMA-HA generated 99mTc-MAMA-BA when incubated in the presence of living
liver slices. However, 99mTc-MAMA-HA remained intact whenthe experiments were performed in the presence of 2-bromooctanoate, an inhibitor for β-oxidation.24 These findings indicatedthat 99mTc-MAMA-HA was recognized as a substrate for β-oxidation by the liver. On these bases, 99mTc-MAMA-derivatives ofdodecanoic acid (DA) and hexadecanoic acid (HDA) were alsosynthesized to estimate whether similar chemical design isapplicable to develop 99mTc-labeled fatty acid analogs recognizedas substrates for β-oxidation in myocardium. In biodistribution
studies, 99mTc-MAMA-HDA showed the maximum heat/blood
ratio of 3.6 at 2 min post-injection. These kinetics were similar
to those of [125I]iodophenylpentadecanoic acid. Metabolicstudies supported that 99mTc-MAMA-HDA was metabolized by
β-oxidation in the body.25 More recently, Lee et al. synthesized8-[99mTc]cyclopentadienyltricarbonyltechnetium 8-oxooctanoic
acid (99mTc-CpTTOA; Figure 6B). This organometallic technetium compound was also metabolized by the liver to generate
4-cyclopentadienyl counterpart.26 Thus, although further studies are required, these studies suggest that 99mTc complexes may
be recognized as substrates for energy production when appropriate structures are given.
Recently, tremendous efforts are being made to apply organometallic technetium and rhenium complexes to radiopharmaceutical. Alberto and co-workers published a new atomosphericsynthesis for complexes [MX3(CO)3]+ (M= Tc or Re; X= Cl orBr).27 More recently, Dyszlewski et al. developed a freeze-dry
formulation for the preparation of the 99mTc(CO)3(OH)3 core inaqueous solution.28 Further details of the organomtallic technetium complexes are found in recent review by Schibli.29
Cyclopentadienyl (Cp) 99mTc(I) and 186Re(I) tricarbonyl complexes [CpM(CO)3] (M = Tc or Re) constitute another interesting
precursors for 99mTc and 186 /188 Re radiopharmaceuticals.
CpTc(CO)3 is a kinetically inert, lipophilic core to which biomolecules can be appended through modification of the Cp ring.
Spradau et al. reported a unique synthetic procedure forCpRe(I)(CO)3 by means of a double ligand transfer reaction,
which can be applicable to 99mTc(I).30 The CpTc(CO)3 was applied
to labeling proteins, peptides31 and an estradiol derivative.32
As a part of works to develop 99mTc and 186/188Re-labeling
reagent of low molecular weight polypeptides based on renal
brush border strategy (Figure 9), 33 we investigated in vivo
metabolism of [188Re]cyclopentadienyltricarbonylrhenium([188Re]CpTR-COOH). This compound was quite stable inmurine plasma. When injected to mice, [188Re]CpTR-COOH

OOH P OHC OH
OH P OHO

Figure 7. Chemical structures of polyphosphonate ligands (A) pyrophosphate, (B) methylenediphosphonate (MDP), (C) hydroxymethylenediphosphonate (HMDP), (D) 1-hydroxyethylidenediphosphonate(HEDP), and (E) [186Re]CpTR-Gly-APD.

180 J. Nucl. Radiochem. Sci., Vol. 6, No. 3, 2005
Blood

Blood-Brain-Barrier

Brain

K1

Lipophilic
Radiotracer

Lipophilic
Radiotracer

k2

×Hydrophilic
Metabolite

TargetEnzymes

k3

k4

Arano

Hydrophilic
Metabolite

Figure 8. Chemical design of radiotracers based on metablic trapping principle. For measuring blood flow, k3 should be much larger
than k2. However, an appropriate rate balance between k2 and k3 isrequired to determine k3.
Renal Brush Border Enzymes
Glycyl-lysine sequence

Peptide

O
O

H
N

N

O

HOOC

*

I

S

N
H

O

Radioiodinated Peptide
O
HOOC

N
H

*

I

Urinary
Excretionm-iodohippuric acid

Renal Cells

Figure 9. Chemical design of radiolabeled low molecular weight
polypeptides for low renal radioactivity. The chemical linkage (glycyl-lysine) is cleaved by brush border enzymes present on the lumenof renal tubules before the polypeptide is internalized into renal cells.
The resulting iodohippuric acid is rapidly excreted into urine.

a significant delay in blood clearance and high radioactivity levelsin the kidney were observed especially with 186Re-HEDP. Thesefindings suggest that both specific activities and affinities to renaltransport systems would play crucial roles in bone accumulation
and blood clearance of 186Re-labeled BPs. These findings would
also provide a good basis for further design of 99mTc- and 186/188Relabeled bisphosphonate that possess pharmacokinetics more suitable to diagnosis and radiotherapy.
5. Conclusion
Over the past 30 years, technetium chemistry has contributed to the development of a variety of 99mTc radiopharmaceuticals that are currently being used in clinical studies. During
these times, significant knowledge has become available in thedesign of radiopharmaceuticals. The metabolic trapping strategy constitutes a representative approach to the design (Figure8).37 Chemical design of radiolabeled low molecular weight
polypeptides utilizing renal brush border enzymes for low renal
radioactivity levels constitutes another example of the design(Figure 9).38 Future combination of the radiopharmaceuticaldesign and technetium chemistry would pave the way to molecular imaging of a variety of disorders with 99mTc radiopharmaceuticals. The development of a new 99mTc radiopharmaceuticalis a multidisciplinary effort and should need the collaborationof researchers in a variety of chemical and nuclear medicine
fields.
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