-
Massachusetts Institute of Technology
Department of Chemistry
Inorganic Division
Design and Synthesis of BoronicAcid Adducts of Technetium
Dioxime Complexes for CerebralTissue Radioimaging
Outside Research Proposal
Author:
Jonathan “Jo” Melville
Adviser:
Yogesh “Yogi” Surendranath
April 29, 2019
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Contents
1 Abstract 1
2 Background and Significance 1
2.1 99mTc Radiopharmaceutical Design . . . . . . . . . . . . . .
. . . . . . . 2
2.2 BATOs: Structure and Function . . . . . . . . . . . . . . .
. . . . . . . . 3
2.2.1 Synthesis and Structure . . . . . . . . . . . . . . . . .
. . . . . . 4
2.2.2 BATO Hydrolysis . . . . . . . . . . . . . . . . . . . . .
. . . . . . 4
2.2.3 Exploiting BATO Hydrolysis for Cerebral Trapping . . . . .
. . . 5
3 Project Goals 5
3.1 Synthesis of BATO Complexes . . . . . . . . . . . . . . . .
. . . . . . . . 5
3.2 Evaluating Hydrolysis Rates . . . . . . . . . . . . . . . .
. . . . . . . . . 8
3.3 Measuring Complex Lipophilicity . . . . . . . . . . . . . .
. . . . . . . . 8
3.4 Measuring In Vivo Blood Perfusion . . . . . . . . . . . . .
. . . . . . . . 9
4 Summary and Future Directions 10
References 10
List of Figures
1 Common Clinical 99mTc Radiotracers . . . . . . . . . . . . . .
. . . . . . 2
2 Generic BATO Structure . . . . . . . . . . . . . . . . . . . .
. . . . . . . 3
3 Mechanism for BATO Ligand Hydrolysis . . . . . . . . . . . . .
. . . . . 4
4 Proposed Boronate Moieties . . . . . . . . . . . . . . . . . .
. . . . . . . 6
5 Proposed Dioxime Moieties . . . . . . . . . . . . . . . . . .
. . . . . . . . 7
6 Proposed Halide and Pseudohalide Moieties . . . . . . . . . .
. . . . . . 8
-
1 Abstract
Boronic acid adducts of technetium dioximes (BATOs) are a class
of technetium com-
pounds which have shown promise for radiotracer imaging of
cerebral and myocardial
tissue. These heptacoordinate complexes consist of a TcIII core,
three chelating dioxime
ligands and an axial chloride ligand, singly capped by a
noncoordinating boronic acid.
These complexes, of the general formula [TcCl(dioxime)3BR], are
small, neutral, and
lipophilic, qualities which make them capable of crossing the
highly-selective blood-brain
barrier (BBB). Under physiological conditions, the axial
chloride ligand hydrolyses to a
hydroxide via a well-studied transformation that modestly
decreases the lipophilicity of
the complex. Previously investigated BATOs display hydrolysis
half-lives on the order
of 10-20 minutes; however, given the rapidity of human blood
perfusion in the brain, the
half-life of this hydrolysis must be on the order of 1-2 minutes
in order to effectively se-
quester [TcOH(dioxime)3BR] within the cerebrum. Herein, we
propose synthetic routes
to a suite of BATOs, exploiting synthetic handles on the boronic
acid, chelating dioxime,
and axial ligand in order to maximize the rate of ligand
hydrolysis and the change in
lipophilicity it evinces. Target compounds will be evaluated for
ex vivo hydrolysis rates
and lipophilicities, leading into in vivo cerebral tissue
extraction and biodistribution
studies in rats. These studies will provide insights into the
relationship between BATO
lipophilicity and hydrolysis rates and cerebral tissue
selectivity, and will pave the way for
the synthesis of new generations of 99mTc
radiopharmaceuticals.
2 Background and Significance
Medical imaging is a critical field of research that is
concerned with visualizing internal
tissues and organs for the purposes of characterizing metabolic
function and diagnosing
disease. Through techniques like Positron Emission Tomography
(PET) or Single Pho-
ton Emission Computed Tomography (SPECT), high-resolution
three-dimensional imag-
ing of target tissues and organ systems can be achieved, with
particular applications for
identifying tumors and visualizing blood flow in the heart or
the brain. Because local
-
cerebral blood flow is closely linked to brain activity and
function, visualizing the perfu-
sion of brain-selective radiopharmaceuticals is an ideal method
to characterize any num-
ber of medically-relevant neuropathologies.[1–3]
2.1 99mTc Radiopharmaceutical Design
(a) 99mTc-sestamibi (CardioliteR©): acardiac blood perfusion
imaging
agent for distinguishing healthy frominfarcted myocardium.
(b) 99mTc-teboroxime (CardioTecR©):a cardiac blood perfusion
imaging
agent for distinguishing healthy fromischemic myocardium.
(c) 99mTc-HIDA (CholetecR©,HepatoliteR©, TechneScan-HIDAR©):
a
motif for several commonhepatobiliary imaging agents.
(d) 99mTc-ECD (NeuroliteR©): acerebral perfusion imaging
agent,
used for evaluation of stroke.
Figure 1. A selection of 99mTc radiopharmaceuticals approved by
the FDA for clinical useshowcases the dependence of organ
specificity on the specific structural properties of the
coordination complex.[4, 5]
99mTc is by far the most ubiquitous radioisotope used in modern
diagnostic nuclear
medicine.[6] Its nuclear properties are ideal for medical
imaging, and its accessible pro-
duction by a 99Mo/99mTc generator makes it affordable for
regular diagnostic use – in
fact, over 90% of the diagnostic scans performed in the United
States utilize 99mTc in
some capacity. Moreover, because the specific blood perfusion
characteristics and tissue
selectivities of a given radiopharmaceutical can vary
drastically, the synthesis and char-
acterization of novel 99mTc complexes is of acute interest to
the field of nuclear medicine,
as the specific uptake profile of a given complex will allow it
to uniquely image certain
2
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subsets of the body.[4]
It is the ligand scaffolding that is primarily responsible for
determining the pharma-
cokinetic propreties of the generated radiotracer. As seen in
Figure 1, which depicts a
smörg̊asbord of clinical radiotracers, a wide variety of
ligands and Tc oxidation states
are used pharmaceutically to induce selectivity for specific
tissues or organ systems.[7]
Technetium complexes are known to exist in every oxidation state
from -1 to +7, and
all but Tc–I and Tc0 find use in some clinical
radiopharmaceutical.[8]. The ligand struc-
ture also is subject to substantial variation: 99mTc
radiocomplexes can be octahedral,
square pyramidal, tetrahedral, trigonal bipyramidal, or
heptacoordinate; anionic, neu-
tral, or cationic; even 99mTc pianostool complexes have been
synthesized and evaluated
for radiopharmaceutical efficacy.[8–11]
2.2 BATOs: Structure and Function
Figure 2. General structure of a BATO complex
[TcX(dioxime)3BR’].
Boronic acid adducts of technetium dioximes (BATOs) are a class
of compounds that
have the potential to produce a new generation of cerebral
imaging radiotracers. These
complexes are small, neutral, and lipophilic, making them ideal
for crossing the blood-
brain barrier (BBB), and their core structure (Figure 2) is ripe
with positions for pro-
cedural modification. In particular, the axial X group is
capable of substitution by hy-
droxide under physiological conditions, a process that could
potentially serve as a handle
for a potential lipophilicity-altering hydrolysis to ensure BATO
retention in cerebral tis-
sue (Section 2.2.2). Despite this, only a small subset of the
possible BATO structural
motifs have been explored. Only one BATO complex –
99mTc-teboroxime (Figure 1b)
– is a clinically-approved radiotracer agent, and then only for
myocardium imaging.[12–17]
3
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2.2.1 Synthesis and Structure
All reported BATOs possess a characteristic heptacoordinate
structure approximating a
monocapped trigonal prismatic structure, with the six ligating
oxime nitrogens forming
the vertices of the prism and a halide singly capping the
structure. The Tc–N distance is
about 2.05Å on the capped end, and about 2.15Å on the uncapped
end.[9] Following the
synthesis of the dioxime ligand by condensation of hydroxylamine
onto a α,β-diketone,
the BATO can be synthesized in high yield in a one-pot reaction,
by the reduction of
TcO4– by SnII in the presence of the dioxime ligands and a
boronic acid, at a low pH
and 100◦C. The reaction proceeds first through a tin-capped
[Tc(dioxime)3(μ-OH)SnCl3]
intermediate which is cleaved in acid to form uncapped
TcCl(dioxime)3, which can adduct
with a boronic acid to form the final BATO complex.[12]
2.2.2 BATO Hydrolysis
The axial X ligand, most commonly chloride, is subject to
exchange by a competitive
anion.[18, 19] Physiologically, this manifests as a substitution
of axial chloride for a hydroxyl
group with a pKa between 7.0 and 7.4, suggesting in vivo
interconversion between the
TcCl and TcOH species. This hydrolysis is believed to occur via
an SN1cB mechanism
(Figure 3), where a bridging oxime is deprotonated concomitant
with chloride loss,
producing a neutral six-coordinate intermediate to which
hydroxide can add to form the
TcOH BATO complex.[20]
Figure 3. Mechanism for chloro-hydroxy axial ligand exchange on
a BATO via an SN1cBmechanism.
4
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2.2.3 Exploiting BATO Hydrolysis for Cerebral Trapping
Because TcOH complexes are less lipophilic than their
corresponding TcCl complexes,
they are less capable of diffusing across the BBB. Preliminary
biodistribution studies
indicate that the cerebral uptake selectivities of TcOH
complexes can be anywhere from
10-100× lower than those of their corresponding TcCl
complexes.[18] Unfortunately, the
in vivo rate of this hydrolysis is too slow for most known BATO
complexes to effectively
sequester TcOH within cerebral tissue; half-lives of hydrolysis
range from 9-21 minutes,
while studies of cerebral blood perfusion indicate that rates as
low as 1-2 minutes are
necessary to ensure effective cerebral trapping.[21–23]. Despite
this, there has been little
investigation as to how BATO complexes could be rationally
designed to maximize the
rate of ligand hydrolysis and change in lipophilicity thereby
evinced. Rather, almost
all well-characterized BATO complexes contain one of the same
two dioxime ligands
(dimethylglyoxime (DMG) or cyclohexanedione dioxime (CDO)), one
of the same two
axial halide ligands (chloride or bromide), and simple
alkylboronic acids.[24]
3 Project Goals
Therefore, this proposal will seek to accomplish the following
goals:
1. Synthesize and characterize a suite of BATO complexes.
2. Evaluate in vitro hydrolysis rates for these complexes.
3. Assess the change in lipophilic character evinced by
hydrolysis.
4. Determine the effect of the former two parameters on in vivo
organ selectivity and
perfusion characteristics.
3.1 Synthesis of BATO Complexes
We propose synthetic routes towards a suite of BATO complexes
that will answer defini-
tively to what degree steric and electronic factors govern the
rate of axial ligand hydro-
5
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lysis. While Jurisson, et. al. invoke “long-range inductive
effects”[18] to explain the cor-
relation between boronic R’ group size and the rate of hydroxide
substitution on the
other side of the molecule, citing a similar outer-sphere
boronate-iron(II) clathrochelate
complex,[25] we find it unlikely that i -butylboronate and
methylboronate moieties would
differ strongly enough in electron-donating character to induce
an order-of-magnitude de-
crease in hydrolysis rate. Rather, it is conceivable that a
bulkier boronate R’ group is ca-
pable of inhibiting the deprotonation of the adjacent oxime,
thereby slowing the forma-
tion of the SN1cB intermediate for BATO hydrolysis. To test this
hypothesis, we aim to
synthesize a series of BATOs pictured in Figure 4, using
commercially available boronic
acids. Boric acid and mesitylboronic acid will provide a strong
control set for the influ-
ence of steric hindrance on hydrolysis rate, while
p-methoxyphenylboronic acid and p-
nitrophenylboronic acid will evaluate whether inductive
electronic effects play a role.
Figure 4. Proposed BATO structures to assess the role of
boronate sterics and electronics onhydrolysis rate.
Modulation of the dioxime ligand (Figure 5) will also provide
valuable informa-
tion about the nature of BATO hydrolysis, as well as potential
routes towards more-
selective radiotracers. By stretching the definition of ‘oxime’
slightly and synthesizing
the sulfur and nitrogen analogs of DMG, we will determine the
effects that modulat-
ing the pKa of the oxime protons will have on BATO hydrolysis.
We would expect the
dimethylthioglyoxime to have more acidic protons than the base
dimethylglyoxime, re-
ducing the barrier to initial SN1cB deprotonation, while the
butanedionedihydrazone ana-
log will have less acidic protons and presumably lower SN1cB
reactivity, leading to a de-
6
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crease in the rate of axial ligand hydrolysis. Meanwhile, the
dioximes formed from bis(p-
methoxyphenyl)butanedione and bis(trifluoromethyl)butanedione
will display greatly dif-
ferent donor character towards the Tc center, which may affect
the favorability of for-
mation of the SN1cB intermediate. While our proposed dioxime
analogs are not com-
mercially available, their butanedione condensation precursors
are reported compounds
with straightforward one- or two-step syntheses from commercial
compounds, and they
are known to chelate metals in a similar clathrate-like
fashion.[26–32].
Figure 5. Proposed BATO structures to assess the role of
‘dioxime’ pKa and electronics onhydrolysis rate.
Finally, modulation of the axial X ligand (Figure 6) has the
potential to both af-
fect the rate of BATO hydrolysis and the change in lipophilicity
effected by the conver-
sion. While, in an SN1cB mechanism, the leaving group character
of the axial ligand may
not be expected to substantially affect the rate of hydrolysis,
inductive electronic effects
can still conceivably lead to increased hydrolysis rate.
Assuming the relatively noncoor-
dinating OTf– anion will bind to technetium in a reasonably
analogous manner, it may
result in a highly labilized and activated BATO complex with a
drastically reduced hy-
drolysis half-life. Meanwhile, substitution with I– , CN– , and
SH– , all polarizable and
lipophilic anions of varying leaving group character, will
evince a greater change in com-
plex lipophilicity upon hydrolysis, potentially allowing for
greater selectivity of the result-
ing BATO complex for cerebral tissue perfusion. While the I– ,
CN– , and SH– analogs
7
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will be synthesizable by nucleophilic substitution on the TcCl
complex,[19] synthesis of
the OTf– analog will require acidic cleavage of the tin-capped
[Tc(dioxime)3(μ-OH)SnCl3]
species by triflic acid due triflate’s non-nucleophilic
nature.
Figure 6. Proposed BATO structures to assess the role of axial
ligand lipophilicity andleaving group character on hydrolysis rate
and cerebral tissue selectivity.
3.2 Evaluating Hydrolysis Rates
Once the desired BATO derivatives are synthesized, kinetic
studies of ex vivo hydrolysis
rates can be performed using HPLC and NMR spectroscopy. Target
BATO complexes,
dissolved in ethanol, will be added to aqueous buffer solutions
at various physiological
pHs and incubated at 37◦C, and TcCl:TcOH fractions will be
determined by the resulting
HPLC chromatograms.[18] The hydrolysis will also be observed by
time-dependent 1H and
99Tc NMR spectroscopy, as well as in situ UV/Vis absorbance
measurements.[33]
3.3 Measuring Complex Lipophilicity
Measuring the lipophilicities of our target complexes will prove
less trivial, as lipophilicity
can sometimes prove difficult to quantify. For our purposes,
however, we can use reverse-
8
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phase HPLC retention times as a reasonable stand-in. Comparing
the retention time tR
of our complexes to the retention time t0 of a non-retained
standard (such as nitrate), we
can calculate the capacity factor k′:
k′ =tR − t0
t0
We can then convert this capacity factor into a more general
expression of lipophilicity,
logP (log of the octanol/water partition ratio), by calibrating
our HPLC with compounds
with known logP values. We can then determine the conversion
relationship between
logP and log k′ for our instrument, allowing for quantification
of lipophilicities of our
target complexes. Comparing the logP values for the TcX
complexes to those of the
hydrolysed TcOH complex, we can determine the magnitude of the
change in lipophilicity
evinced by hydrolysis.
3.4 Measuring In Vivo Blood Perfusion
The final step in our proposal is an in vivo study of
biodistribution and cerebral extrac-
tion, which will require the use of 99mTc BATOs from a
99Mo/99mTc generator. In rats,
biodistribution can be determined by injecting a known amount of
radioactivity into a
major vein, sacrificing the rat after a set amount of time, and
assaying target tissues for
radioactivity.[34, 35] Cerebral extraction studies are more
involved, requiring the rate of
cerebral blood flow to be controlled by manual syringe pumping.
By simultaneously in-
jecting a rat with a target BATO complex along with a control
radiotracer lacking cere-
bral tissue selectivity (such as 133Xe or 85Sr),[36] the
cerebral extraction fraction E at a
given timepoint can be calculated by decapitating the rat and
measuring the ratio of the
control and target tracer signals in the brain and the
blood:
E =(cpm99mTc/cpm85Sr)brain
(cpm99mTc/cpm85Sr)blood,
where ‘cpm’ denotes count per minute radiation signal assigned
to either 99mTc or 85Sr
in either rat brain or blood.[22, 37]
9
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In this study, our primary goals will be to determine the
relation between axial halide
lipophilicity and cerebral tissue extraction, the relationship
between supporting ligand
steric and electronic character and axial ligand hydrolysis
rate, and, finally, the relation-
ship between ex vivo hydrolysis rate and cerebral tissue
retention.
4 Summary and Future Directions
We have proposed a series of rational modulations to a
well-known 99mTc structural
motif which remains largely unexplored in the contemporary
literature. We propose that
modulation of the chelating ligand, the adducting boronic acid,
and the axial halide
ligand can be used as a handle to manipulate the lipophilicity
and the rate of axial
ligand hydrolysis, in accordance with previous kinetic analyses
on these compounds. As
the lipophilicity of the complexes determines the ease of
perfusion across the blood-brain
barrier, and the rate of hydrolysis determines whether the
complexes will be sequestered
within the brain, these modulations should enable greater
selectivity and retention within
cerebral tissue and provide synthetic handles for further
rational development of cerebral
imaging radiotracers. Having determined the axial ligand with
the highest in vivo cerebral
perfusion rate and the supporting ligand framework with the
highest rate of axial ligand
hydrolysis, a natural next step will be to synthesize the BATO
complex with both of
these ligands and assess its in vivo cerebral tissue perfusion.
While autoradiography and
emission tomography studies, especially in humans, are well
beyond the scope of this
proposal, the development of novel BATO complexes may lay the
groundwork for future
studies as potential next-generation cerebral imaging
radiopharmaceuticals.
References
[1] Dilworth, J. R.; Parrott, S. J. Chem. Soc. Rev. 1998, 27,
43–55.[2] Alberto, R. In Comprehensive Coordination Chemistry II ;
McCleverty, J. A.,
Meyer, T. J., Eds.; Pergamon: Oxford, 2003; pp 127–270.[3]
Sattelberger, A. P.; Bryan, J. C. In Comprehensive Organometallic
Chemistry II ;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier:
Oxford, 1995; pp 151–166.
[4] Jurisson, S.; Berning, D.; Jia, W.; Ma, D. Chem. Rev. 1993,
93, 1137–1156.
10
-
[5] Kikuchi, T.; Okamura, T.; Wakizaka, H.; Okada, M.; Odaka,
K.; Yui, J.; Tsuji, A. B.;Fukumura, T.; Zhang, M.-R. J. Cereb.
Blood Flow Metab. 2014, 34, 585–588.
[6] Swanson, D. P.; Thrall, J. H.; Chilton, H. M.
Pharmaceuticals in Medical Imaging ;Macmillan Pub. Co.: New York,
N.Y., 1990.
[7] Mazzi, U. Technetium-99m Pharmaceuticals ; CRC Press: New
York, New York,2007; pp 7–58.
[8] Baldas, J. In Advances in Inorganic Chemistry ; Sykes, A.
G., Ed.; Academic Press,1994; Vol. 41; pp 1–123.
[9] Tisato, F.; Refosco, F.; Bandoli, G. Coord. Chem. Rev. 1994,
135-136, 325–397.[10] Schwochau, K. Angew. Chem. Int. Ed. 1994, 33,
2258–2267.[11] Banerjee, S. R.; Maresca, K. P.; Francesconi, L.;
Valliant, J.; Babich, J. W.; Zubi-
eta, J. Nucl. Med. Biol. 2005, 32, 1–20.[12] Linder, K. E.;
Malley, M. F.; Gougoutas, J. Z.; Unger, S. E.; Nunn, A. D.
Inorg.
Chem. 1990, 29, 2428–2434.[13] Jurisson, S. Drugs Fut. 1990, 15,
1085.[14] Hansch, C.; Clayton, J. M. J. Pharm. Sci. 1973, 62,
1–21.[15] Walovitch, R. C.; Cheesman, E. H.; Maheu, L. J.; Hall, K.
M. J. Cereb. Blood Flow
Metab. 1994, 14 Suppl 1, S4–11.[16] Nowotnik, D. P.
Radiopharmaceuticals: Chemistry and Pharmacology, 1st ed.; CRC
Press: New York, New York, 1992; pp 37–95.[17] Vallabhajosula,
S.; Zimmerman, R. E.; Picard, M.; Stritzke, P.; Mena, I.; Hell-
man, R. S.; Tikofsky, R. S.; Stabin, M. G.; Morgan, R. A.;
Goldsmith, S. J. J. Nucl.Med. 1989, 30, 599–604.
[18] Jurisson, S. S.; Hirth, W.; Linder, K. E.; Di Rocco, R. J.;
Narra, R. K.; Nowot-nik, D. P.; Nunn, A. D. Int. J. Rad. Appl.
Instrum. B 1991, 18, 735–744.
[19] Thompson, M.; Nunn, A. D.; Treher, E. N. Anal. Chem. 1986,
58, 3100–3103.[20] Hirth, W.; Jurisson, S.; Linder, K.; Feld, T.;
Nunn, A. D. J. Label. Compd. Radio-
pharm. 1989, 26, 48–49.[21] Neirinckx, R. D.; Canning, L. R.;
Piper, I. M.; Nowotnik, D. P.; Pickett, R. D.;
Holmes, R. A.; Volkert, W. A.; Forster, A. M.; Weisner, P. S.;
Marriott, J. A. J.Nucl. Med. 1987, 28, 191–202.
[22] Nowotnik, D.; Hirth, W.; Jurisson, S. J. Nucl. Med. Allied
Sci. 1989, 33, 310.[23] Lassen, N. A.; Henriksen, L.; Paulson, O.
Stroke 1981, 12, 284–288.[24] Treher, E. N.; Francesconi, L. C.;
Gougoutas, J. Z.; Malley, M. F.; Nunn, A. D.
Inorg. Chem. 1989, 28, 3411–3416.[25] Robbins, M.; Naser, D.;
Heiland, J.; Grzybowski, J. Inorg. Chem. 1985, 24, 3381–
3387.[26] Tsai, C.-H.; Shih, C.-J.; Wang, W.-S.; Chi, W.-F.;
Huang, W.-C.; Hu, Y.-C.; Yu, Y.-
H. Appl. Surf. Sci. 2018, 434, 412–422.[27] Franek, W.; Claus,
P. K. Monatsh. Chem. 1990, 121, 539–547.[28] Moore, L. O.; Clark,
J. W. J. Org. Chem. 1965, 30, 2472–2474.[29] Essers, M.; Haufe, G.
Encyclopedia of Reagents for Organic Synthesis ; American
Cancer Society, 2006.[30] Zhai, Y.; Su, Z.; Jiang, H.; Rong, J.;
Qiu, X.; Tao, C. Tet. Lett. 2019, 60, 843–846.[31] Drawe, H. Chem.
Ztg. 1978, 102, 137–148.[32] Drawe, H. Chem. Ztg. 1978, 102,
213–224.[33] Nunn, A. D. Radiopharmaceuticals: Chemistry and
Pharmacology, 1st ed.; CRC
Press: New York, New York, 1992; pp 97–140.
11
-
[34] Deutsch, E.; Hirth, W. J. Nucl. Med. 1987, 28,
1491–1500.[35] Blower, P. J.; Singh, J.; Clarke, S. E. J. Nucl.
Med. 1991, 32, 845–849.[36] Ohmomo, Y.; Francesconi, L.; Kung, M.
P.; Kung, H. F. J. Med. Chem. 1992, 35,
157–162.[37] Nowotnik, D. P.; Canning, L. R.; Cumming, S. A.;
Harrison, R. C.; Higley, B.; Nech-
vatal, G.; Pickett, R. D.; Piper, I. M.; Bayne, V. J.; Forster,
A. M.; Weisner, P. S.;Neirinckx, R. D.; Volkert, W. A.; Troutner,
D. E.; Holmes, R. A. Nucl. Med. Com-mun. 1985, 6, 499.
[38] Johnstone, E. V.; Yates, M. A.; Poineau, F.; Sattelberger,
A. P.; Czerwinski, K. R.J. Chem. Educ. 2017, 94, 320–326.
[39] Abram, U.; Alberto, R. J. Braz. Chem. Soc. 2006, 17,
1486–1500.[40] Spies, H.; Scheller, D. Inorg. Chim. Acta 1986, 116,
1–4.[41] Francesconi, L. C.; Graczyk, G.; Wehrli, S.; Shaikh, S.
N.; McClinton, D.; Liu, S.;
Zubieta, J.; Kung, H. F. Inorg. Chem. 1993, 32, 3114–3124.[42]
North, A. J.; Hayne, D. J.; Schieber, C.; Price, K.; White, A. R.;
Crouch, P. J.;
Rigopoulos, A.; O’Keefe, G. J.; Tochon-Danguy, H.; Scott, A. M.;
White, J. M.;Ackermann, U.; Donnelly, P. S. Inorg. Chem. 2015, 54,
9594–9610.
[43] Kasten, B. B.; Ma, X.; Cheng, K.; Bu, L.; Slocumb, W. S.;
Hayes, T. R.; Trabue, S.;Cheng, Z.; Benny, P. D. Bioconjug. Chem.
2016, 27, 130–142.
[44] Ichimura, A.; Heineman, W. R.; Vanderheyden, J. L.;
Deutsch, E. Inorg. Chem.1984, 23, 1272–1278.
[45] Linder, K. E.; Chan, Y. W.; Cyr, J. E.; Nowotnik, D. P.;
Eckelman, W. C.;Nunn, A. D. Bioconjug. Chem. 1993, 4, 326–333.
[46] Johannsen, B.; Berger, R.; Brust, P.; Pietzsch, H.-J.;
Scheunemann, M.; Seifert, S.;Spies, H.; Syhre, R. Eur. J. Nucl.
Med. 1997, 24, 316–319.
[47] Linder, K. E.; Chan, Y. W.; Cyr, J. E.; Malley, M. F.;
Nowotnik, D. P.; Nunn, A. D.J. Med. Chem. 1994, 37, 9–17.
[48] Pelaez, A. Polyhedron 1982, 1, 827–830.[49] Busch, D. H.;
Bailar, J. C. J. Am. Chem. Soc. 1956, 78, 1137–1142.[50] Stoufer,
R. C.; Busch, D. H. J. Am. Chem. Soc. 1956, 78, 6016–6019.[51]
Franklin, K. J.; Lock, C. J. L.; Sayer, B. G.; Schrobilgen, G. J.
J. Am. Chem. Soc.
1982, 104, 5303–5306.[52] O’Connell, L. A.; Pearlstein, R. M.;
Davison, A.; Thornback, J. R.; Kronauge, J. F.;
Jones, A. G. Inorg. Chim. Acta 1989, 161, 39–43.[53] Irwin, G.
H.; Preskorn, S. H. Brain Res. 1982, 249, 23–30.[54] Feld, T.;
Nunn, A. D. J. Label. Compd. Radiopharm. 1989, 26, 274–276.[55]
Volkert, W. A.; Hoffman, T. J.; Seger, R. M.; Troutner, D. E.;
Holmes, R. A. Eur.
J. Nucl. Med. 1984, 9, 511–516.[56] Mazzi, U.; Bandoli, G.;
Nicolini, M. Technetium and Rhenium in Chemistry and
Nuclear Medicine 3 ; Verona : Cortina International ; New York :
Raven Press, 1990.[57] Szimhardt, N.; Wurzenberger, M. H. H.;
Zeisel, L.; Gruhne, M. S.; Lommel, M.;
Klapötke, T. M.; Stierstorfer, J. Chem. Eur. J. 2019, 25,
1963–1974.[58] De Ligny, C. L.; Gelsema, W. J.; Tji, T. G.; Huigen,
Y. M.; Vink, H. A. Int. J. Rad.
Appl. Instrum. B 1990, 17, 161–179.[59] All Mail -
[email protected] - Gmail.
https://mail.google.com/mail/u/0/#all.
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AbstractBackground and Significance99mTc Radiopharmaceutical
DesignBATOs: Structure and FunctionSynthesis and StructureBATO
HydrolysisExploiting BATO Hydrolysis for Cerebral Trapping
Project GoalsSynthesis of BATO ComplexesEvaluating Hydrolysis
RatesMeasuring Complex LipophilicityMeasuring In Vivo Blood
Perfusion
Summary and Future DirectionsReferences