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

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

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

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

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

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

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

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

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

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.

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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