Communications
doi.org/10.1002/ejic.202100163
derivatives are stable for several weeks at room temperature
mechanistic action as is already successfully employed in
Neurolite, a commercial 99mTc brain imaging perfusion agent.[12]
Cyclopentadiene 9 was synthesized by reacting 1 with N-(o-
methoxy)phenylpiperazine in the presence of NaI and diisopro-
°
and for several months at À 25 C.
Based on the work of Hatanaka et al. and previous work of
our group,[6,8] Cp 1 was synthesized from the α-bromoketone 2
and the Wittig salt 3 under alkaline conditions in 76% yield.
Bromoketone 2 was synthesized in 65% yield by treating 4 with
Br2 at low temperatures. Compound 3 was synthesized in three
steps from 3,3-dimethylacrylic acid according to a literature
procedure.[8c] The carboxilic acid was esterified with EtOH,
brominated with N-bromosuccinimid (NBS) and azobis
(isobutyronitril) (AIBN), and subsequently treated with PPh3 in
toluene to deliver 3.
°
pylethylamine (DIPEA) in DMF at 120 C for 4 h in 33% yield.
°
Subsequent reaction with [Re2(CO)10] in o-xylene at 220 C for
15 min using μ-wave heating gave 7 in 39% yield (Scheme 2).
[Re2(CO)10] was employed as Re-precursor. This precursor works
very well for this kind of reaction as we showed in a previous
study.[8c] Other Re-precursors have thus not been investigated.
Compound 8 was synthesized by reacting 1 with tris(4-
methoxyphenyl)phosphine in the presence of NaI and DIPEA,
delivering 10, with subsequent Re coordination with [Re2(CO)10]
as Re source. The ester functionality in 8, compared to [99mTc]6,
is available for conjugation to a second bioactive moiety such
as a cytotoxin, or its hydrolysed form simply increases its water
solubility for better bioavailability and improved pharmacology.
For expanding the scope and the nature of coupling
reactions, the chloride in 1 was replaced by an azide group (11,
Scheme 3). This azide group can later be employed in Click
chemistry with an alkyne-derivatized lead structure of choice.
Click reactions are widely used in medicinal chemistry but are
not so common in radiopharmaceutical chemistry.[13] Since a
plethora of biologically active compounds with alkinyl groups is
commercially available, a screening by correspondingly deriva-
tizing 11 becomes easily feasible.
Compound 1 was successfully employed in the synthesis of
two precursors to derivatives of known drug candidates
(Figure 1, compounds [99mTc]5 and [99mTc]6) in one step, or to
cold Re derivatives of the corresponding drug candidate in two
steps. The first derivative (7) was inspired by cytectrene
[
99mTc]5, which was reported by Zenati et al. in 2017 for brain
imaging.[9] The structure of the second derivative (8) had its
origin in cytectrene [99mTc]6, a compound developed by Li et al.
in 2018 for the imaging of multi-drug resistance (MDR) in
cancer cells.[10] Phosphonium compounds also showed applica-
tion in targeting mitochondria. A number of 99mTc compounds
have been described for this purpose, albeit not with
cytectrene-based complexes.[11] The newly synthesized deriva-
tives 7 and 8 deviate from the imitated lead structures [99mTc]5
and [99mTc]6 primarily in additional substituents located on the
cyclopentadienyl ligand. Depending on the biological target,
these additional substituents may serve different functions.
Compound [99mTc]5 crossed the blood-brain barrier (BBB),
however, it displayed low first-pass uptake into the brain and
fast clearance thereof.
Compound 11 was synthesized along two pathways. Direct
reaction of 1 with NaN3 emphasises the role of 1 as a fast
modifiable scaffold, but 11 was obtained in very poor yield only
(2% from 4). A more promising approach is the direct
introduction of the azide in a first step by reacting 4 with a
slight excess NaN3. The resulting organo-azide 12 is then
treated with Br2 at low temperatures, yielding the bromoketone
13 in 68% yield. 13 is reacted with 3 along a traditional Wittig-
type reaction to give 11 in moderate yields (33% from 4). The
second method to introduce the azide earlier is favourable
since it increases the overall yield substantially.
Azide 11 readily undergoes Click reactions with phenyl-
acetylene as model in the presence of CuII and sodium
ascorbate, yielding triazole 14. Formation of the corresponding
Re complex 15 was achieved by reacting 14 with [Re2(CO)10] in
good yield (78%).
Conceptually, the ester group on the cytectrene moiety
should allow the compound to accumulate in the brain by
passing the blood-brain-barrier (BBB) with the ester group
staying intact. In the brain, the ester is hydrolysed to the
corresponding carboxylic acid, which traps the compound in
the brain. This leads to longer retention times in a similar
Scheme 2. Modification of 1 by nucleophilic substitution with subsequent Re
complex formation; i) 1-(o-methoxy)phenyl piperazine, DIPEA, NaI, DMF, μ-
Figure 1. Design of new [η-5(C5H5)MI(CO)3] (M=Re, 99mTc) complexes for
wave, 120 C, 4 h, 33%; ii) [Re2(CO)10], o-xylene, μ-wave, 220 C, 15 min, 39%;
°
°
°
medicinal applications based on previously reported drug candidates
iii) tris(4-methoxyphenyl)phosphine, NaI, DMF, μ-wave, 120 C, 90 min, 80%;
[
99mTc]5 and [99mTc]6.
iv) [Re2(CO)10], o-xylene, μ-wave, 220 C, 15 min, 70%.
°
Eur. J. Inorg. Chem. 2021, 1611–1614
1612
© 2021 Wiley-VCH GmbH
Lengacher, Raphael
