Novel bifunctional [16]anes4-derived chelators for soft radiometals

Article abstract of DOI:10.3390/molecules26154603

The field of targeted radionuclide therapy is rapidly growing, highlighting the need for wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional chelators. These allow for the practical bioconjugation to targeting vectors, in turn enabling radiolabeling. The [16]andS₄ macrocycle has been reported to chelate a number of relevant soft metal ions. In this work, we present a procedure for synthesizing [16]andS₄ in 45% yield (five steps, 12% overall yield), together with a selection of strategies for preparing bifunctional derivatives. An ester-linked N-hydroxysuccimide ester (NHS, seven steps, 4% overall yield), an ether-linked isothiocyanate (NCS, eight steps, 5% overall yield) and an azide derivative were prepared. In addition, a new route to a carbon-carbon linked carboxylic acid functionalized derivative is presented. Finally, a general method for conjugating the NHS and NCS derivatives to a polar peptide (octreotide) is presented, by dissolution in water:acetonitrile (1:1), buffered to pH 9.4 using borate. The reported compounds will be readily applicable in radiopharmaceutical chemistry, by facilitating the labeling of a range of molecules, including peptides, with relevant soft radiometal ions.

Full text of DOI:10.3390/molecules26154603

molecules
Communication
Novel Bifunctional [16]aneS4-Derived Chelators for Soft Radiometals
Natan J. W. Straathof , Charlotte B. Magnus, Fedor Zhuravlev and Andreas I. Jensen *
Department of Health Technology (DTU Health Tech), Technical University of Denmark (DTU), Frederiksborgvej
399, 4000 Roskilde, Denmark; njwst@dtu.dk (N.J.W.S.); chbusk@dtu.dk (C.B.M.); fezh@dtu.dk (F.Z.)
* Correspondence: atije@dtu.dk
Abstract: The field of targeted radionuclide therapy is rapidly growing, highlighting the need for
wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and
palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional
chelators. These allow for the practical bioconjugation to targeting vectors, in turn enabling radiola-
beling. The [16]andS4 macrocycle has been reported to chelate a number of relevant soft metal ions.
In this work, we present a procedure for synthesizing [16]andS4 in 45% yield (five steps, 12% overall
yield), together with a selection of strategies for preparing bifunctional derivatives. An ester-linked
N-hydroxysuccimide ester (NHS, seven steps, 4% overall yield), an ether-linked isothiocyanate (NCS,
eight steps, 5% overall yield) and an azide derivative were prepared. In addition, a new route to
a carbon-carbon linked carboxylic acid functionalized derivative is presented. Finally, a general
method for conjugating the NHS and NCS derivatives to a polar peptide (octreotide) is presented,
by dissolution in water:acetonitrile (1:1), buffered to pH 9.4 using borate. The reported compounds
will be readily applicable in radiopharmaceutical chemistry, by facilitating the labeling of a range of
molecules, including peptides, with relevant soft radiometal ions.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Keywords: sulfur containing macrocycles; bifunctional chelators; bio-conjugation; radiation therapy
Citation: Straathof, N.J.W.; Magnus,
C.B.; Zhuravlev, F.; Jensen, A.I. Novel
Bifunctional [16]aneS4-Derived
Chelators for Soft Radiometals.
1. Introduction
Molecules 2021, 26, 4603. https://
doi.org/10.3390/molecules26154603
The field of nuclear medicine has seen remarkable growth in recent years, in particular
within oncology. Here, radionuclides emitting ionizing radiation are used for either diagno-
Academic Editors: Andrea Trabocchi
sis or therapy, the two modalities in turn combined under the umbrella of theranostics [
New theranostic platforms, such as PSMA targeted ligands for prostate cancer, have driven
the surge in interest [
], with the therapeutic 177Lu-PSMA-617 just completing clinical
1].
and Elena Lenci
2
Received: 6 July 2021
Accepted: 26 July 2021
Published: 29 July 2021
phase 3 with a positive outcome [3].
In nuclear medicine, radiopharmaceuticals are typically constructed as conjugates
of receptor-specific vectors with radionuclides. For radiometals, this requires the use of
chelators, capable of trapping the radiometal ions as stable complexes (Figure 1A). This
strategy can effectively deliver radionuclides to target tissues such as tumors. Diagnostic
imaging by positron emission tomography (PET) is most commonly performed using
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with regard to jurisdictional claims in
published maps and institutional affil-
iations.
radionuclides such as 15O, 13N, 11C, 68Ga and 18F [
4,5]. Other PET radiometals of more
limited use include 64Cu, 55Co and 86Y. Concomitantly, targeted radionuclide therapy
(TRT) typically focuses on eradicating cancer metastases via alpha, beta or Auger electron
radiotherapy (AeRT) [
considered responsible for up to 90% of cancer-related deaths [
6
–
8
]. Metastasis is a major reason for cancer recurrence and is
], making TRT highly
9
Copyright:
© 2021 by the authors.
relevant. AeRT is considered particularly promising for eradicating micro-metastases, due
to the unique short range and potency of Auger electron emissions [10–14].
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 4603. https://doi.org/10.3390/molecules26154603
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4603
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Figure 1.
application in targeted radiotherapy and radiodiagnostics. (
novel [16]aneS4 bifunctional chelators reported in this manuscript.
(
A
) Bifunctional [16]aneS4 chelators as a general strategy for soft radiometal complexes for bio-conjugation, with
B) Examples of reported [16]aneS4 chelator derivatives and the
Current therapeutic radionuclides of high interest include the beta particle emitters
177Lu, 131I, 90Y and 67Cu, and the alpha particle emitters 225Ac, 227Th and 211At. The most
common Auger electron emitters used in current research are 123/125I, 67Ga, 111In and
99mTc, largely as a result of their availability and established radiochemistry [13
,15–20].
Radiometals that form soft Lewis acid cations are also available. These soft radiometals
have a particularly high binding affinity to sulfur-containing ligands (vide supra). However,
the range of soft radiometals relevant to theranostics is rarely investigated, due to a lack
of well-suited bifunctional chelators with active chemical handles that can be practically
conjugated to targeting vectors (Figure 1A). Suitable soft radiometals for AeRT include
isotopes of platinum (193mPt and 195mPt) and rhodium (103mRh) [21 22]. Additionally, 103Pd
,
and 105Rh, an X-ray emitter and a beta particle emitter, respectively, also have potential use
in TRT.
To address this deficiency, we identified [16]aneS4 (1,5,9,13-tetra thiacyclohexadecane)
as a potential chelator for late transition radiometals. [16]aneS4 belongs to a larger class
of crown ethers, which includes widely used oxygen donor macrocycles, such as 18-
crown-6 [23]. While oxygen-based crown ethers strongly bind alkali and alkaline earth
metal ions, their thioether analogues show distinct preference for the much softer late
transition metals [24]. The complexation of [16]aneS4 (and derivatives thereof) with
various transition metals has been studied intensively (Table 1) [25–40]. Its application in
radiopharmaceutical chemistry remains limited, however, and to date only a few examples
have demonstrated complexation between a soft radiometal and [16]aneS4. Lyczko et al.
successfully demonstrated the formation of a stable Rh(III) complex formed via the use
of 1,5,9,13-tetrathiacyclohexadecane-3,11-diol and 1,5,9,13-tetrathiacyclohexadecane-3-ol
(respectively, [16]aneS4-diol and [16]aneS4-ol) [28]. This complex was used for binding
radioiodine and 211At using the chelated Rh as coordination center. Moreover, [16]aneS4

Molecules 2021, 26, 4603
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has been studied in relation to 105Rh for in vivo bio-distribution [26
,
30]. To highlight the
potential application of such sulfur-containing macrocycles, an overview of the reported
metal-[16]aneS4 complexes is provided in Table 1. Accordingly, expanding the chemical
space of bifunctional [16]aneS4 derived chelators would be beneficial, especially in the
context of soft radiometal delivery. In this report we present a synthetic framework for the
preparation of bifunctional [16]aneS4 chelators (Figure 1B, bottom).
Table 1. Overview of selected reported metal [16]aneS4–ligand complexes (MLC) and their potential application in
radionuclide diagnostics or therapy, see SM for a more detailed overview. Both reported radionuclides and relevant
unreported radioisotopes of the same element are included.
Entry
Chelator
Metal
Isotopes
(Potential) Application a
Ref.
103Rh, 103mRh, 105Rh
X = 211At, 131I, 123I, 124
60Cu, 64Cu, 67Cu
191Pt, 193mPt, 195mPt
103Pd
1
2
3
4
5
6
7
[16]aneS4, [16]aneS4-ol, [16]aneS4-diol
[16]aneS4-ol
Rh
RhX
Cu
Pt
Pb
Sb
MLC, TRT
MLC, TRT, SPECT, PET
MLC, PET, TRT, SPECT
TRT
[26,27,29]
[28]
[19,32,34,35]
[20,37,38]
[21]
I
[16]aneS4
[16]aneS4
[16]aneS4-3-octyoxyl
[16]aneS4
MLC, TRT
119Sb
TRT
[20,39]
[19,20,40]
94mTc, 99mTc
[16]aneS4
Tc
TRT, PET, SPECT
a
MLC = metal–ligand complex, TRT = targeted radiotherapy, PET = positron emission tomography, SPECT = single-photon emission
computed tomography.
2. Results and Discussion
The synthesis of [16]aneS4 was initially reported by Meadow and Reid in 1934, who
identified the difficulty of the formation of rings containing more than 12 members (e.g.,
[16]aneS4 was obtained in 1% yield under the reported conditions) [31]. As mentioned
above, the synthesis of [16]aneS4-diol and [16]aneS4-ol, was disclosed later, using a mul-
tistep approach to prepare the asymmetric analogues of [16]aneS4 [28,29]. This strategy
originated from the seminal report on an alternative synthetic strategy for sulfur-containing
macrocycles by Ochrymowycz, in 1973 [32]. While the overall yield was slightly improved
(5% yield), the effects observed during ring formation were of particular importance, sug-
gesting that, for example, a chloro leaving groups and lower solvent polarity favored larger
ring structures.
On this backdrop, several different strategies were considered, accounting for synthetic
practicality and compound stability. To broaden the application of the new macrocyclic
chelator derivatives, three different linker types were prepared (Figure 1B, bottom), all
with the potential to further the use of soft radiometals in nuclear medicine. Our syn-
thetic approach started with the multistep synthesis to [16]aneS4-ol
adapted from Lyczko and Li [28 29], and the crucial findings from the reports of Meadow,
Reid and Ochrymowycz [31 32]. Starting with 1,3-dithiopropane and 3-chloropropanol,
gave 1,11-dihydroxy-4,8-dithiaundecane in moderate yield (76%, Figure 2). Transfor-
7, using a method
,
,
1
mation of the hydroxyls to thiols was accomplished with consecutive tosylation of the
hydroxyl groups, thioacetylation and hydrolysis, which give linear product 1,11-dithio-
4,8-dithiaundecane
with 1,3-dichloropropan-2-ol and 1,11-dithio-4,8-dithiaundecane
4
in 34% yield over 3 steps. The final macrocyclization was performed
, at high dilution and
4
slow addition (multiple hours) of a mixture of both reactants in DMF and with Cs2CO3
as base (see SM for full details). Gratifyingly, this procedure gave the desired macrocycle
[16]aneS4-ol 7 (45% yield, 12% overall yield).
With macrocycle [16]aneS4-ol
conjugation sites (Figure 3). Previously, [16]aneS4-ol
ethylacetate by Lyczko [28]. In order to construct an ester-linked analogue, [16]aneS4-ol
was conjugated with succinic anhydride to give carboxylic acid (73% yield). Ester-linked
7
in hand, we began the construction of the functional
7
was functionalized with -bromo
α
7
8
chelators could have a potentially faster catabolism in vivo, which has been recognized
as enabling a faster radionuclide clearance, which is potentially desirable for long-lived
therapeutic radionuclides [41]. The carboxylic acid intermediate
transformed into the corresponding NHS ester as compound
8
9
was then activated and
(52% yield, 4% overall

Molecules 2021, 26, 4603
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yield in 7 steps). In addition, [16]aneS4-ol
7
was decorated with N-Boc-3-aminopropyl
methane sulfonate to give the N-protected intermediate 11 (78% yield). This compound
was then deprotected under acidic conditions and transformed into the corresponding
isothiocyanate via consecutive reaction of the amine with N,N0-thiocarbonyldiimidazole
under alkaline conditions (see SM for more details). Via this route, isothiocyanate 13 was
obtained in a relative straightforward fashion (65% yield, 5% yield in 8 steps). Notably,
the amino intermediate 12 was also transformed directly into the corresponding azido
compound 23 using a diazo transfer reagent (75% yield). Azides are extremely useful due
to their practical bioconjugation via azide–alkyne cycloadditions under various conditions
in vitro and in vivo [42].
Figure 2. Synthesis of [16]aneS4-ol (see SI for further details).
The route towards [16]aneS4-isothiocyanate 13 proved to be sufficient to be a versatile
synthetic framework for alternative strategies. While the overall yield of [16]aneS4-ol
could be improved further by using the suggestions from Meadow, Reid and Ochrymowycz
(vide infra) [31 32], we questioned whether it was possible to directly prepare 13 from in a
7
,
7
single step reaction with isothiocyanatobenzyl bromide or 1-bromo-3-isothiocyanatopropane.
Both isothiocyanatobenzyl bromide or 1-bromo-3-isothiocyanatopropane are commercially
available [43], and combining these with Ag2CO3 as a concomitant base and halogen
abstraction reagent, we questioned whether it would be possible to transform [16]aneS4-ol
7, directly into the corresponding [16]aneS4-isothiocyanate 13 (Figure 3, bottom section).
Notably, direct alkylation of [16]aneS4-ol with 3-bromo propaneisothiocyanate or 4-
7
(bromomethyl) phenyl-isothiocyanate, resulted in only trace amounts of desired products.
In a further attempt to shorten the synthetic route, and to improve the overall product
yield, an alternative route was considered (Figure 4). Inspired by Bagchi et al. [34], 1,3-
diiodopropane and two equivalents of thiacyclobutane (thietane) were mixed and stirred
◦
with KI, K2CO3 in DMF for several days at 45 C. This gave 1,11-diiodo-4,8-dithiaundecane
6
in good yield (87–95% yield, 1.5 gram scale). At this point we wanted to evaluate
whether we could use dihydrolipoic acid (DHLA) as the 1,3-dithio coupling partner in the
final macrocyclization. DHLA can be prepared quantitatively from -lipoic acid under
α
mild reducing conditions; NaBH4, NaHCO3 in H2O (see SI for details) [44]. The fact
that LA is commercial, inexpensive and relatively facile to transform into its protected
and reduced analogues (compounds 13 and 14, 75% and 82% yield, respectively) is very
attractive. Despite numerous efforts, macrocyclication with DHLA or 13 were unsuccessful,
and resulted in no reaction or complex inseparable mixtures. Cyclization with benzyl
protected DHLA analogue 14 gave the desired macrocycle 17 in modest macrocyclization
yield (15%). However, in light of the low overall yields of the formations of bifunctional
chelators derived directly from [16]aneS4-ol 7, macrocyclization with DHLA to form 22
appears to be an attractive gateway to functionalizable derivatives. Further attempts to
improve the yield of this step were unsuccessful, and it was observed that 1,11-diiodo-

Molecules 2021, 26, 4603
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4,8-dithiaundecane
inert atmosphere (argon) at
these observations, we hypothesized that
6
was unstable and could not be stored for several days, even under
−
20 ◦C (see SM for more details and discussion). Based on
6
rapidly decomposes due to the presence of
iodide, via a reversed sulfonylation degradation pathway or via polymerization. The
instability of these compounds was also attributed to external factors such as light and heat,
including the presence of heavy halogens (such as iodine), which was also observed by
Meadow and Reid [31]. To study the effects of different (halogen) leaving groups, the chloro
and bromo analogues of 1,11-dihalogen-4,8-dithiaundecane were prepared. 1,11-dichloro-
4,8-dithiaundecane 19 and 1,11-dibromo-4,8-dithiaundecane 20 were also prepared via
different routes (Figure 4 bottom, see SI for more details) [45,46]. Unfortunately, these
alternative coupling electrophiles, with a bromo, chloro or tosyl leaving group, respectively,
did not yield any significant improvement over the previous obtained macro cyclization
with 18 and 19.
Figure 3. Synthesis of bifunctional [16]aneS4 chelator derivatives, including the NHS ester, isothio-
cyanate and azide derivative.

Molecules 2021, 26, 4603
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Figure 4. Alternative synthesis of bifunctional [16]aneS4 chelator.
With the successful preparation of four novel [16]aneS4 chelator derivatives, of which
three with a reactive functional chemical handle, specifically, [16]aneS4-NHS , [16]aneS4-
NCS 13, [16]aneS4-N3 23, we elected and 13, to be conjugated to octreotide, as a proof-
9
9
of-concept for further conjugation studies. Octreotide is a mimic of natural somatostatin,
which is a growth hormone-inhibiting hormone, which regulates the endocrine system,
affecting neurotransmission and cell proliferation [47]. Octreotide is used in various thera-
peutic settings, such as carcinoid tumor care, treating hepatic metastases and palliation.
Further, it represents the most widely used peptide vector in current radionuclide ther-
anostics, together with its close analogue octreotate. Octreotide is therefore a relevant
candidate for bioconjugation. Briefly, octreotide was dissolved in aqueous borate buffer
◦
(80 mM) at pH = 9.4, and mixed in a 1-to-7 molar ratio with
(400
9
or 13 in MeCN at 50 C
µ
L, aq. buffer:MeCN, 1:1, v/v, see SM for more details). These reactions’ conditions
resulted in clear solutions with no precipitation of either chelator derivatives or peptide.
Both conjugates were successfully grafted to octreotide as judged by MALDI-TOF mass
spectrometry analysis (Figure 5). This preliminary conjugation study indeed demonstrates

Molecules 2021, 26, 4603
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that the newly prepared [16]aneS4 analogues can be conjugated to compounds of high
interest under relevant reaction conditions, with optimization of these conditions being a
subject for future research.
Figure 5. Bioconjugation of
9 and 13 with octreotide (hypothetical selective N-terminal functionaliza-
tion shown for clarity).
3. Materials and Methods
Materials, methods and copies of NMR spectra of all compounds are attached in the
Supplementary Materials (SM).
4. Conclusions
In conclusion, a number of novel bifunctional chelators were synthetically prepared
for application in soft radiometal theranostics. The chelator, a [16]aneS4 crown thioether
macrocycle, has the potential to chelate a large number of soft radiometals, including
isotopes of rhodium, palladium and platinum, which are of significant interest in targeted
radionuclide therapy. A number of functional handles were attached to the chelator,
including an NHS ester, isothiocyanate (NCS), azide and carboxylic acid. For all of which
the overall yield was moderately improved in respect to previous procedures, 4% in seven
steps, 5% in eight steps, 6% in eight steps and 11% in five steps, respectively. In addition,
attempts were made to shorten the synthetic preparation of these bifunctional chelators,
resulting in a novel carbon–carbon linked derivative. Both the [16]aneS4-NHS and the
[16]aneS4-NCS were successfully conjugated to octreotide, a mimic of natural somatostatin,
as an initial proof-of-concept for further bio-conjugation studies.
Supplementary Materials: The following are available online, Table S1: Overview of reported and
potential applications of [16]aneS4 chelator-metal complexes and derivatives. Figure S1: Structures
of commonly used [16]aneS4 chelator derivatives., Figure S2: Compound overview used in the
macrocyclization screening between DHLA-derivatives (14, 16 and 18) and electrophiles (2, 5, 6 and
19), Table S2: Overview of screening.
Author Contributions: Conceptualization, A.I.J., C.B.M. and N.J.W.S.; methodology, A.I.J., C.B.M.,
N.J.W.S. and F.Z.; writing—original draft preparation, N.J.W.S.; writing—review and editing, A.I.J.,
F.Z. and N.J.W.S.; project administration, N.J.W.S. and A.I.J.; funding acquisition, A.I.J. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Independent Research Fund Denmark, grant number
DFF-6111-00392.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

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