Don’t Try This at Home
This is my 15 minutes of fame. It occurred a long time ago in the late seventies. I was a graduate student in the School of Chemical Sciences at the University of Illinois-Urbana in John Katzenellenbogen’s group. We were trying to make radiopharmaceuticals that bound to estrogen receptor containing breast tumors. This would allow you to image a tumor and determine its receptor status non-invasively. The goal was to make an estrogen labeled with fluorine-18, a positron emitter. The chemistry to make this was very complicated, and it took another student after my time a few more years to do it. He’s now at NIH in their Nuclear Medicine department. But we figured we could use the hard gamma emitter bromine-77 as the label, because it was available from the LAMPF at Los Alamos (since closed down), I might be able to develop some chemistry to incorporate the label into an estradiol precursor, and the gamma camera could get some crude, non-tomographic images…sort of a proof of concept.
One
night, in a drunken fog, I got the stupid idea that a mild, in-situ oxidant
could kick bromide up to an electrophilic species that would react with the
enol diacetate of estradiol to make 16alpha-bromoestrone-3-acetate. Reduction
and purification gets you 16alpha-bromoestradiol-17beta. LAMPF bromine-77 came
as a basic aqueous solution of sodium bromide-77 mixed in with a bunch of
sodium chloride, nitrates, and nearly every other element in the periodic up to
Mo. It was made by a spallation reaction with energetic protons on Mo metal
(read: beat the shit out of), so it wasn’t too pure. This is why the above idea
was stupid. In my stupor, I could care less, so I pre-incubated buffered acetic
acid (sodium acetate) with 30% hydrogen peroxide for a half an hour, shot an
aliquot into a suspension/solution of said enoldiacetate and sodium bromide in
THF/ether, sat around for a half hour, worked up, and went home. NMR the next
morning said 16alpha-bromoestrone-3-acetate. Far out. As my character Moe would
say, What da fuck happened?
Well,
hit the lit. I found two early 50’s papers that shed light on what was
happening in this witches’ brew. Acetic acid and hydrogen peroxide will make
very low concentrations of peroxyacetic acid if it sits long enough at room
temperature. If nothing else decomposes the peroxy acid, bromide will attack
the distal oxygen to make hypobromous acid and kick out acetic acid to be
oxidized to more peroxyacid. You never have enough peroxyacid around to chew up
the substrate, and hypobromous acid reacts with the enol acetate to give the
bromoketone like a shot.
This reaction got me out of grad school.
It’s fairly general, and works for iodide and chloride as well. Not fluoride. The reaction rates for the three halides are what you would expect. We hoped that the chlorination would be slow (it was by a factor of 104), and chloroproducts would be separable from bromoproducts on the HPLC (they were).
Almost home. OK, hit it with LAH at –20o. It knocks off the bromo, gives a mixture of alpha and beta estradiols, maybe even some 16, 17-epoxide. Shit. The ketone reduction is fast, but the debromination isn’t much slower. Run the reduction using a clarified 1.2M THF solution of LAH (aluminum hydroxides and oxides may promote dehalogenation) at -80o, then quench at –80o, warm it up, and finish the Fieser quench. The bromide stays on, HPLC provides 16alpha-bromoestradiol-17beta, but there’s another problem…..
This problem is unique to high specific activity radiochemistry. The specific activity of the sodium bromide-77 is around 2000 Ci/mmol. The mass of a 500 mCi sample is vanishingly small. You can’t do a stoichiometric reaction, so you take the enol acetate in large excess, which was for practicality, 200 ug. You’re gonna have a lot of unreacted starting material hanging around. Unfortunately, the reduction product of the starting material was estrone, which tailed into our product HPLC elution window. Double shit. What’s goin’ on…hit the lit…all the way back to Nystrom when he was in my situation at the U of Chicago during the war…
If you reduce an enol acetate with LAH and quench, you get the ketone. But, if you quench in such a way that you protonate the enol and keep some of the LAH around, the ketone tautomer goes down to the alcohol.
It’s an in-situ double reduction. We did this by quenching with a slight excess of sec-butanol in THF at –80o, then warming up and finishing the quench. Estradiol is easy to get rid of on HPLC. Home free!!!
OK, now for the radiochemistry. Journey to the never-never land of Mike Welch’s lab at the Mallinckrodt Institute of Radiology at Barnes Hospital, St Louis. Run everything behind lead shields using mirrors. (Hard gammas give you cataracts.) It works. We make the compound. Shoot up some rats, put them under the camera. It concentrates in rat mammary tumors. We give it to a human subject with breast cancer. It lights up her tumors. It’s the first scintigraphic image of a human breast tumor obtained by a biochemically-based functional imaging agent. I get my PhD.
Update, 2002
Illness ended my scientific career. It was real while it lasted. Perhaps our ability to sort out biological processes in vivo will lead someday to an understanding of the mechanism by which ALS ends careers. Maybe, when that happens, people will remember that I was part of the group of scientists that got this stuff off the ground. Here is my contribution to the world’s knowledge.
Publications of Stephen G. Senderoff,
Ph. D. 1980-2001
1. Synthesis and preliminary
in vitro characterisation of a F-18- labelled analogue of SB209670, a PET
radioligand for the endothelin receptor. Johnstrom P, Landvatter SW,
Senderoff SG, Clark JC, Pickard JD, Ohlstein EH ,Davenport AP British Journal of Pharmacology (2001) 133:
99P
2. Borohydride exchange resin as an alternative
method for deuterium labeling. Landvatter,
Scott W.; Schauer, Douglas J.; Games, Keith T.; Mack, James F.; Senderoff,
Stephen G.; Killmer, Lewis B., Jr. Radiochemistry Section, SmithKline Beecham
Pharmaceuticals, King of Prussia, PA, USA. Editor(s): Pleiss, Ulrich; Voges,
Rolf. Synthesis and Applications of
Isotopically Labelled Compounds, Proceedings of the International Symposium,
7th, Dresden, Germany, June 18-22,2000 (2001),
Meeting Date 2000,
130-133. Publisher: John Wiley & Sons Ltd., Chichester, UK CODEN:
69CIJC
Conference written in English. AN 2002:174755 CAPLUS
Abstract
An easy alternative method for introducing deuterium
into mols. is described. Copper sulfate activated borodeuteride exchange resin
redns., when carried out in methanol-d4, selectively reduces bromoaroms. with
high incorporation of deuterium. This method is rapid, mild, highly selective
and is compatible with a wide variety of functional groups. Simple filtration
gives products of high purity.
3. A novel synthesis of
[O-methyl-14C]dextromethorphan: utility of the vinyloxycarbonyl group. Senderoff, S. G.; Landvatter, S. W.; Heys,
J. R. Radiochemistry Section UW2830,
Department of Synthetic Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA. J. Labelled Compd. Radiopharm. (2000), 43(13), 1283-1288. CODEN:
JLCRD4 ISSN: 0362-4803. Journal
written in English. AN
2000:805993 CAPLUS
Abstract
A novel, selective approach to
[O-methyl-14C]Dextromethorphan is presented.
The key feature is protection of 3-hydroxymorphinan at nitrogen and
oxygen with the vinyloxycarbonyl group.
This allows selective O-deprotection and methylation without competing
nitrogen quaternization. The N-vinyloxy
carbonyl group is converted to the desired Me group by lithium aluminum hydride
redn.
4. Direct tritium labeling of multifunctional
compounds using organoiridium catalysis. 2. Shu, A. Y. L.; Saunders, D.; Levinson, S. H.; Landvatter, S. W.;
Mahoney, A.; Senderoff, S. G.; Mack, J. F.; Heys, J. R. Radiochemistry, SmithKline Beecham
Pharmaceuticals, King of Prussia, PA,
USA. J. Labelled Compd.
Radiopharm. (1999), 42(8),
797-807. CODEN: JLCRD4 ISSN: 0362-4803. Journal written in
English. CAN 131:299124 AN 1999:525826 CAPLUS
Abstract
A variety of complex compds. were labeled with tritium
gas by catalytic exchange in the presence of catalyst precursors
[(cod)Ir(dppe)]BF4 or [(cod)Ir(py)(PCy3)]BF4.
In most cases, predictable regioselectivity and high specific activities
are achieved. These results are
compared in some cases to the results of labeling related compds. with
[(cod)Ir(PPh3)2]BF4. Preredn. of the
catalyst precursors in situ with hydrogen allows the use of smaller quantities
of tritium gas and reduces the amt. of radioactive waste. Two or more compds. can be labeled
simultaneously as mixts. then sepd. in the HPLC purifn. step to increase compd.
throughput.
5. Direct tritium labeling of multifunctional
compounds using organoiridium catalysis. Chen, W.; Garnes, K.T.; Levinson, S.H.; Saunders, D.; Senderoff,
S.G.; Shu, A.Y.L.; Villani, A.J.; Heys, J.R.
Radiochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA. J. Labelled Compd. Radiopharm. (1997),
39(4), 291-298. CODEN: JLCRD4 ISSN: 0362-4803.
Journal written in English. CAN 127:4735 AN 1997:272097
CAPLUS
Abstract
The tritium exchange labeling of a variety of complex
compds. is achieved in the presence of catalyst precursor [(cod)Ir(PPh3)2]BF4
and limited amts. of tritium gas. The
regioselectivity of exchange is high and consistent with empirical rules
previously obsd. High specific activity
levels are often achieved, usually with specific aryl C-H bonds. However, remarkably efficient exchange
occurs in certain N-alkyl groups.
Studies of intermol. inhibition of catalytic exchange suggest reasons
why larger amts. of complex are sometimes required to label complex mols.;
nevertheless, significant amts. of label incorporation into substrates can be
achieved even starting with small amts. of labeling gas.
6. Synthesis of the enantiomers and three racemic
metabolites of Carvedilol labeled to high specific activity with tritium. Senderoff, S. G.; Villani, A. J.;
Landvatter, S. W.; Garnes, K. T.; Heys, J. R. Dep. Synth. Chem.,
SmithKline Beecham Pharm., King
of Prussia, PA, USA.
J. Labelled Compd. Radiopharm.
(1993), 33(12), 1091-105.
CODEN: JLCRD4 ISSN: 0362-4803. Journal
written in English. CAN
120:270010 AN 1994:270010 CAPLUS
Abstract
Carvedilol (SK&F 105517) (I) possesses unique
cardiovascular activity, and is under development for indications such as
angina and hypertension. Tritium
labeled enantiomers of Carvedilol and racemates of three metabolites were
needed for pharmacol. and drug metabolic studies. These compds. were synthesized by catalytic tritium-halogen
exchange using tritium gas and 10% palladium-on-carbon catalyst. The precursors were polyhalogenated in the
carbazole ring. Direct electrophilic
bromination of the enantiomers of Carvedilol gave precursors that were
converted to the corresponding tritiated final products by catalytic tritium
halogen exchange. Bromination of
4-(2,3-epoxypropyloxy)-9H-carbazole gave an intermediate that was converted to
the halogenated precursors of the racemic metabolites. Elaboration of this intermediate,
1,3,6-tribromo-4-(2,3-epoxypropyloxy)-9H-carbazole, to the desired metabolite
precursors was achieved by nucleophilic epoxide opening with suitably
functionalized N-benzyl aryloxyethylamines.
Catalytic tritium-halogen exchange upon the brominated metabolite
precursors was accompanied by cleavage of N- and O-benzyl protecting
groups. Radiochem. purities of all
tritiated final products were greater than 98% after preparative HPLC. Specific activities of the final products,
detd. by mass spectrometry, ranged from 35 to 76 Ci/mmol. Optical purity of the Carvedilol
enantiomers, detd. by chiral HPLC, was greater than 99%.
7. Synthesis of a tritium-labeled azaspirane:
SK&F 105685. Landvatter, Scott W.;
Senderoff, Stephen G.; Heys, J. Richard.
Dep. Synth. Chem., SmithKline
Beecham Pharm., King of Prussia, PA,
USA. J. Labelled Compd.
Radiopharm. (1993), 33(12),
1113-17. CODEN: JLCRD4 ISSN: 0362-4803. Journal written in
English. CAN 120:191458 AN 1994:191458 CAPLUS
Abstract
SK&F 105685 (I) was prepd. in tritium labeled from
by two different methods. Moderate
specific activity material was obtained via sodium borotritide redn. on an
iminium perchlorate precursor which itself had been derived from I. High specific activity material was obtained
via catalytic redn. of a terminal double bond.
8. Deuterium exchange labeling of substituted
aromatics using [IrH2(Me2CO)2(PPh3)2]BF4. Heys, J. R.; Shu, A. Y. L.; Senderoff, S. G.; Phillips, N.
M. Synthetic Chem. Dep., SmithKline Beecham Pharm., King of Prussia, PA, USA. J. Labelled Compd. Radiopharm. (1993),
33(5), 431-8. CODEN: JLCRD4 ISSN: 0362-4803.
Journal written in English. CAN 119:159817 AN 1993:559817
CAPLUS
Abstract
Deuterium exchange labeling expts. were conducted on
several series of compds., including para-substituted benzoate esters 4-RC6H4CO2Et
(R = Me2N, OH, MeO, Me3C, AcO, H, Ph, F, Br, Cl, CO2Et, CF3, cyano, O2N),
para-substituted N,N-dimethylbenzamides 4-RC6H4CONMe2 (R = MeO, H, F, Br, Cl,
CO2Et, CONMe2, CF3, O2N), and mono-para-substituted benzophenones 4-R1C6H4COPh
(R1 = MeO, Me, Cl, CF3), using [IrH2(Me2CO)2(PPh3)2]BF4 as catalyst and
deuterium gas as the source of isotope.
In most cases, labeling was efficient and regioselective, with deuterium
appearing in the positions ortho to the carbonyl-contg. functional group. Apparent from the results with the
mono-para-substituted benzophenones was that, in each case the para-substituted
rings were labeled more rapidly or to a greater extent than the corresponding
unsubstituted rings, regardless of the identity of the substituent.
9. Synthesis of carbon-14 and tritium labeled
analogs of manoalide. Senderoff, S. G.;
Shu, A. Y. L.; Lawrie, K.; Heys, J. R.
Dep. Synth. Chem., Smithkline
Beecham Pharm., King of Prussia, PA,
USA. J. Labelled Compd.
Radiopharm. (1992), 31(7),
519-38. CODEN: JLCRD4 ISSN: 0362-4803. Journal written in
English. CAN 117:171751 AN 1992:571751 CAPLUS
Abstract
Several manoalide analogs,
4-(1-acetyloxyalkyl)-5-hydroxy-2(5H)-furanones I [R = (CH2)nMe, n = 6, 10; R =
(CH2)4Ph] labeled with carbon-14 in the alkyl side chain, were
synthesized. The key step in the
syntheses was singlet oxygenation of 2-trialkylsilyl-4-alkylfurans (II; R1 =
Me, Et) to give the corresponding 4-alkyl-5-hydroxy-2(5H)-furanones I. The carbon-14 label in the side chain was
introduced earlier in the synthesis by reaction of the desired labeled alkyl
Grignard reagent with the appropriate 2-trialkylsilyl-4-furancarboxaldehyde and
trapping of the resulting magnesium alkoxide with acetic anhydride. Labeled n-alkyl Grignard reagents were
obtained by carbonation of the corresponding nor-alkyl bromides using ultrapure
magnesium metal and barium carbonate-14C followed by redn. of the resulting
acid to the alc. Bromination followed by
metalation gave the desired reagents. Manoalide analogs bearing a carbon-14 or tritium label in the
acetyl moiety of the side chain were synthesized by acetylation of the desired
side-chain alc. with acetyl chloride-1-14C, and by acetylation of the desired
alc. with dibromoacetic acid-DCC followed by catalytic halogen-tritium exchange
and completion of the synthesis.
10. Use of the Fujimoto-Belleau reaction for the
efficient preparation of a [phenyl-14C]benzazepine derivative. Heys, J. R.; Senderoff, S. G.. Smith Kline and French Lab., King of Prussia, PA, USA. Editor(s): Baillie, Thomas A.; Jones, John
Richards. Synth. Appl. Isot. Labelled
Cpd. 1988, Proc. Int. Symp.
(1989), Meeting Date 1988, 395-400.
Publisher: Elsevier, Amsterdam,
Neth CODEN: 56OXA8 Conference
written in English. CAN
112:118626 AN 1990:118626 CAPLUS
Abstract
A lecture with 15 refs.
A new and efficient benzazepine synthesis was developed and used to
prep. 7-hydroxy-2,3,4,5-tetrahydro-8-methylsulfonyl-1H-3-benzazepine
methanesulfonate (I, SK&F 103829-J) labeled with 14C in the benzene
ring. The synthetic method centers on a
modified Fujimoto-Belleau sequence, which served to introduce the label via
[14C]-MeMgI and to generate the final carbon skeleton. The substrate for the Grignard addn., enol
lactone, was assembled by a 4-diazobutyrate insertion into N-benzyl-4-pyridone,
followed by hydrolysis and dehydrative ring closure. The Grignard product diketone was subjected to aldol ring
closure, and the resulting enone aromatized to provide 14C-labeled benzazepine
in three steps and an overall yield of 28% from [14C]-MeI. Subsequent transformations produced [14C]-I
in high overall yield.
11. Synthesis of carbon-14 and tritium labeled
dopamine beta-hydroxylase inhibitors of the imidazolinethione type. Senderoff, S. G.; Shilcrat, S. C.; Levinson,
S. H.; Heys, J. R. Dep. Synth.
Chem., Smith Kline and French Lab., King of Prussia, PA, USA. J. Labelled Compd. Radiopharm. (1989),
27(7), 841-9. CODEN: JLCRD4 ISSN: 0362-4803.
Journal written in English. CAN 112:7424 AN 1990:7424
CAPLUS
Abstract
1-[(3,5-Difluoro-4-hydroxyphenyl)methyl]-1,3-dihydro-2H-imidazole-2-thione,
1-[(3,5-difluoro-4-methoxyphenyl)methyl]-1,3-dihydro-2H-imidazole-2-thione, and
1-[(3,5-difluorophenyl)methyl]-1,3-dihydro-2H-imidazole-2-thione (SK&F
102048, SK&F 102055, and SK&F 102698, resp.) were synthesized in
carbon-14 and tritium labeled forms.
Carbon-14 from potassium [14C]thiocyanate was incorporated into the
imidazolethione ring of SK&F 102055 and SK&F 102698 at C(2) by
condensation with
N-(2,2-dimethoxyethyl)-3,5-difluoro-4-methoxybenzenemethanamine or
N-(2,2-dimethoxyethyl)-3,5-difluorobenzenemethanamine. Treatment of SK&F [2-14C]102055 with
boron tribromide gave SK&F [2-14C] 102048.
Tritiated SK&F 102048 was synthesized by sodium [3H]borohydride
redn. of N-(3,5-difluoro-4-methoxyphenylmethylene)-2,2-dimethoxyethanamine,
followed by condensation with potassium thiocyanate and demethylation with
boron tribromide.
12. A new entry into C7-oxygenated
tetrahydro-1H-3-benzazepines; efficient labeling with carbon-14 in the benzo
ring. Heys, J. Richard; Senderoff, Stephen
G.. Synth. Chem. Dep., Smith Kline and French Lab., King of Prussia, PA, USA. J. Org. Chem. (1989), 54(19), 4702-6.
CODEN: JOCEAH ISSN:
0022-3263. Journal written in English. CAN 111:173966 AN 1989:573966
CAPLUS
Abstract
Addn. of 14CH3MgI to hexahydropyranoazepinone I provided
diketone II in 64% yield (based on 14CH3I).
Base-catalyzed intramol. aldol condensation provided the corresponding
cyclic enone in 93% yield, and aromatization-methylation of the latter gave
[14C]benzazepine III in 47% yield. In
optimized reactions with unlabeled materials, yields for the 3 steps were 80,
100, and 70%, resp. I was prepd. in 44%
overall yield through a diazo insertion reaction initiated by base-induced
decompn. of MeO2CN(NO)(CN2)3CO2Et in the presence of N-benzyl-4-piperidone,
followed by acid hydrolysis of the ester group of the insertion product and cyclization
in Ac2O-AcCl.
13. Synthesis of carbon-14-labeled
6-(4-fluorophenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole. Senderoff, S. G.; Heys, J. R.; Blackburn, D.
W. Radiochem. Dep., SmithKline Beckman Corp., Philadelphia, PA, USA. J. Labelled Compd. Radiopharm. (1987),
24(8), 971-8. CODEN: JLCRD4 ISSN: 0362-4803.
Journal written in English. CAN 108:131653 AN 1988:131653
CAPLUS
Abstract
SKF 86002, the unlabeled title compd. (I; R = 4-FC6H4,
R1 = 4-pyridyl) (II), a nonsteroidal antiinflammatory agent, was prepd. labeled
with 14C at C-1 or C-2,3 from either H2N14CONH2 or Br(14CH2)2Br, resp. The synthetic route, involving the
condensation of an asym. benzoin with thiourea followed by alkylation, gave a
mixt. of II and structural isomer SKF 86055, (I; R = 4-pyridyl, R1 =
4-FC6H4). The 2 products were sepd.
easily by flash chromatog. The use of
Br(14CH2)2Br as the labeling reagent was superior to the use of H2N14CONH2 in
this sequence; the radiolabel was incorporated in the final step of the
synthesis by an alkylation, thus providing greatly increased overall radiochem.
yields.
14. Synthesis of tritium labeled
O-ethyl-D-tyrosine and phenylalanine. Landvatter, Scott W.; Heys, J. Richard; Senderoff, Stephen G.. Smith Kline and French Lab., Philadelphia, PA, USA. J. Labelled Compd. Radiopharm. (1987),
24(4), 389-96. CODEN: JLCRD4 ISSN: 0362-4803.
Journal written in English. CAN 108:112905 AN 1988:112905
CAPLUS
Abstract
Tritium-labeled amino acids I (Boc = Me3O2C; R = 3H, R1
= EtO; R = H, R1 = 3H) were prepd. by treating D-tyrosine or
p-iodophenylalanine derivs. with tritium gas over 5% Pd catalyst. The specific activities of the resp. I were
4-7 and > 35 Ci/mmol.
15. Synthesis And Evaluation Of
Radiopharmaceuticals For Melanoma Delineation. Heindel
ND Emrich
JG Woo
DY, Kaltovich
F, Seoane
P, Senderoff
S, Garnes
K, Landvatter
S Hahnemann University, Department of Nuclear Medicine
and Smith Kline and French Lab.,
Philadelphia, PA, USA.
16. Strategic considerations in the radiosynthesis
of substituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols. Blackburn, Dale; Villani, Anthony;
Senderoff, Steve; Landvatter, Scott; Garnes, Keith. Smith Kline and French Lab.,
Philadelphia, PA, USA.
Editor(s): Muccino, Richard Robert.
Synth. Appl. Isot. Labeled Compd. Proc. Int. Symp., 2nd (1986),
Meeting Date 1985,
309-10. Publisher:
Elsevier, Amsterdam, Neth CODEN: 55BUAT Conference written in
English. CAN 106:84373 AN 1987:84373 CAPLUS
Abstract
Benzazepines I (R-R3 = H; R = R2 = H, R1 = Cl, R3 = OH;
R = R2 = Me, R1 = R3 = H; R = allyl, R1 = Cl, R2 = H, R3 = OH) labeled with 14C
and 3H were prepd.
17. Estrogen receptor-based agents for imaging
breast tumors: binding selectivity as a
basis for design and optimization. Kazenellenbogen, John A.; Heiman, Daniel F.; Senderoff, Stephen
G.; McElvany, Karen D.; Landvatter, Scott W.; Carlson, Kathryn E.; Goswami,
Ramanuj; Lloyd, John E. Sch. Chem.
Sci., Univ. Illinois, Urbana,
IL, USA. Editor(s): Lambrecht, Richard M.; Morcos,
Nabil. Appl. Nucl. Radiochem. (1982),
311-23. Publisher:
Pergamon, Elmsford, N. Y CODEN: 48VFAQ Conference; General Review
written in English. CAN
97:211577 AN 1982:611577 CAPLUS
A review with 32 refs.
18. Methodology for the synthesis and specific
activity determination of 16a-[77Br]-bromoestradiol-17b and 16a-[77Br]-bromo-11b-methoxyestradiol-17b, two estrogen receptor-binding
radiopharmaceuticals. Senderoff, Stephen
G.; McElvany, Karen D.; Carlson, Kathryn E.; Heiman, Daniel F.;
Katzenellenbogen, John A.; Welch, Michael J.
Sch. Chem. Sci., Univ. Illinois, Urbana,
IL, USA. Int. J. Appl. Radiat. Isot. (1982),
33(7), 545-51. CODEN: IJARAY ISSN: 0020-708X.
Journal written in English. CAN 97:163312 AN 1982:563312
CAPLUS
Abstract
16a-[77Br]-bromoestradiol-17b (I) was prepd. from estrone
enol diacetate II by bromination with Na77Br and H2O2-HOAc, followed by redn.
with LiAlH4 to give a mixt. of I and 16a-[77Br]-bromoestradiol-17a from which the desired epimer I can be obtained in 50% overall
radiochem. yield (from Na77Br) by HPLC.
Analogous procedures can be used in the prepn. of 16a-[77Br]-bromo-11b-methoxyestradiol-17b. The effective specific activities of these radiopharmaceuticals,
detd. by binding to the uterine estrogen receptor, are 900-1500 Ci/mmol. Both have high affinity and good binding
selectivity for the estrogen receptor and are useful as imaging agents for
mammary tumors.
19. 16a-[77Br]bromo-11b-methoxyestradiol-17b: a gamma-emitting estrogen imaging agent with high uptake and
retention by target organs. Katzenellenbogen, John A.; McElvany, Karen D.; Senderoff, Stephen
G.; Carlson, Kathryn E.; Landvatter, Scott W.; Welch, Michael J. Univ. Illinois, Urbana, IL, USA.
J. Nucl. Med. (1982), 23(5),
411-19. CODEN: JNMEAQ ISSN: 0022-3123. Journal written in
English. CAN 97:19986 AN 1982:419986 CAPLUS
Abstract
16a-[77Br]Bromo-11b-methoxyestradiol-17b (I), a compd. with high
affinity for the estrogen receptor and with low nonspecific binding, was prepd.
with an effective specific activity of 770-1450 Ci/mmol at the time of
synthesis. In immature female rats,
this compd. is taken up selectively by the uterus and is retained for prolonged
periods. This is presumably due to the
binding of this compd. to the estrogen receptor, as uterine uptake is blocked
selectively by coadministration of an excess of unlabeled estradiol, and
administration of a chase dose of unlabeled estradiol results in a rapid
decrease in activity in the uterus. In
double-label expts. with 16a-[125I]iodoestradiol and I, the 2 compds. showed equally selective
uterine uptake at 1 h, but the Br-labeled compd. became increasingly more selective
at 3 and 6 h. I may prove to be a more
favorable agent for imaging human breast tumors than the previously described
compd., 16a-[77Br]bromoestradiol-17b.
20. In vivo comparison of 16a-[77Br]bromoestradiol-17b and 16a-[125I]iodoestradiol-17b McElvany, Karen D.; Carlson, Kathryn E.;
Welch, Michael J.; Senderoff, Stephen G.; Katzenellenbogen, John A. Sch. Med., Washington Univ., St.
Louis, MO, USA. J. Nucl. Med. (1982),
23(5), 420-4. CODEN: JNMEAQ ISSN: 0022-3123.
Journal written in English. CAN 97:2966 AN 1982:402966
CAPLUS
Abstract
An in vivo comparison of 2 estrogen-receptor-binding
radiopharmaceuticals of high specific activity, 16a-[77Br]bromoestradiol-17b and 16a-[125I]iodoestradiol-17b, was carried out in immature
female rats. The iodoestradiol has
slightly higher uterine uptake in 1 h after injection, whereas the brominated
analog has enhanced uptake at later times.
The similar behavior of the 2 compds. in vivo suggests that estradiol
labeled with 123I, 77Br, and 75Br could be used interchangeably for the imaging
of breast tumors contg. estrogen receptors.
In addn., coinjection of 16a-[125I]iodoestradiol as an internal std. was useful for comparison of
different radiohalogenated estrogens.
21. 16a-[77Br]bromoestradiol:
dosimetry and preliminary clinical studies. McElvany, Karen D.; Katzenellenbogen, John
A.; Shafer, Kenneth E.; Siegel, Barry A.; Senderoff, Stephen G.; Welch, Michael
J. Sch. Med., Washington Univ., St. Louis, MO, USA.
J. Nucl. Med. (1982), 23(5),
425-30. CODEN: JNMEAQ ISSN: 0022-3123. Journal written in
English. CAN 96:213346 AN 1982:213346 CAPLUS
Abstract
An estrogen-receptor-binding radiopharmaceutical, 16a-[77Br]bromoestradiol-17b, has been used successfully at
high specific activity to image carcinogen-induced mammary tumors in rats and
in preliminary studies to image breast tumors in patients. The biodistribution of the labeled estrogen
in rats and its clearance in a monkey were used to est. the radiation-absorbed
doses to a human resulting from administration of the radiopharmaceutical. Preliminary imaging studies in patients with
mammary carcinoma show promising results and warrant further development of
radiolabeled estrogens, particularly those carrying positron emitters that
could permit positron-emission tomog., such as 75Br or 18F.
22. Design, synthesis and biological properties of
estrogen receptor binding breast tumor localizing agents. Senderoff, Stephen Gary. Univ. Illinois, Urbana, IL, USA.
Avail. Univ. Microfilms Int., Order No. DA8203584. (1981), 316 pp. From: Diss.
Abstr. Int. B 1982, 42(9), 3696.
Dissertation written in
English. CAN 96:199982 AN 1982:199982 CAPLUS
23. Scope and limitations of a rapid
radiobromination technique. McElvany, Karen D.; Welch, Michael J.; Katzenellenbogen, John A.;
Senderoff, Stephen G.; Bentley, Glenn E.; Grant, Patrick M. Sch. Med., Washington Univ., St.
Louis, MO, USA. Int. J. Appl.
Radiat. Isot. (1981), 32(6),
411-16. CODEN: IJARAY ISSN: 0020-708X. Journal written in
English. CAN 95:38459 AN 1981:438459 CAPLUS
Abstract
A series of model compds. were labeled with 77Br using
the method for rapid radiobromination of D. J. Malcome-Lawes and S. J. Massey
(1980). Characterization of the
77Br-labeled products showed the technique to be unsuitable for labeling
fragile mols., such as proteins. Thus, the
technique should not be considered a generally applicable radiobromination method;
however, it may be a useful means of attaching radiobromine to some simple
mols. which are not sensitive to oxidative conditions and do not possess
multiple sites for halogenation.
24. 16a-[bromine-77]bromoestradiol-17b: a high specific-activity, gamma-emitting tracer with uptake in
rat uterus and induced mammary tumors. Katzenellenbogen, John A.; Senderoff, Stephen G.; McElvany, Karen
D.; O'Brien, H. A., Jr.; Welch, Michael J.
Univ. Illinois, Urbana, IL,
USA. J. Nucl. Med. (1981),
22(1), 42-7. CODEN: JNMEAQ ISSN: 0022-3123.
Journal written in English. CAN 94:98887 AN 1981:98887
CAPLUS
Abstract
16a-[77Br]bromoestradiol-17b(I) was synthesized by
radiobromination of estrone enoldiacetate.
Tissue uptake studies performed 1 h after administration of I to
immature or mature female rats showed uterus-to-blood ratios of 13, with
nontarget tissue-to-blood ratios ranging from 0.6 to 2. Co-administration of unlabeled estradiol
caused a selective depression in the uterine uptake with no effect on nontarget
tissue uptake. In adult animals bearing
mammary adenocarcinomas induced by DMBA, tumor-to-blood ratios of 6.3 were
obtained, this uptake also being depressed in animals treated with unlabeled
estradiol. I thus has suitable binding
properties and sufficiently high specific activity so that its uptake in
estrogen target tissues in vivo was mediated primarily by the estrogen
receptor. This compd. may also be
suitable for imaging human breast tumors that contain estrogen receptors.
25. Estrogen receptor-based imaging agents. 1.
Synthesis and receptor binding affinity of some aromatic and D-ring
halogenated estrogens. Heiman, Daniel F.;
Senderoff, Stephen G.; Katzenellenbogen, John A.; Neeley, Richard J. Roger Adams Lab., Sch. Chem. Sci., Urbana, IL, USA.
J. Med. Chem. (1980), 23(9),
994-1002. CODEN: JMCMAR ISSN: 0022-2623. Journal written in
English. CAN 93:143547 AN 1980:543547 CAPLUS
Abstract
I and II (R and R1 = H or halogen) were synthesized as
potential estrogen receptor-based imaging agents for human breast tumors. Estrogens bearing an arom. F ortho to a
phenolic OH group were prepd. by the Schiemann reaction on the corresponding Me
esters; other ortho-halogenated estrogens were prepd. by direct
halogenation. Steroidal estrogens
substituted at 16a
position were prepd. by halogenation of estrone 3-acetate (17-enol
acetate) [20592-42-1] followed by
hydride redn., and those substituted at the 16b position were prepd. by epimerization prior to
redn. The binding affinity of these
halogenated estrogens to the uterine estrogen receptor was measured relative to
that of estradiol by a competitive binding assay. All of the monosubstituted ortho-fluorinated estrogens had high
binding affinity for the receptor (64-250% that of estradiol). The monosubstituted and sym. disubstituted
bromo- and iodohexestrols and 2- and 4-substituted estradiols have binding
affinities considerably lower than those of the fluoro compds., the
4-substituted estradiols having affinities greater than the corresponding
2-substituted isomers. Introduction of
a halogen (Cl, Br, I) at the 16a position of 17b-estradiol
results in compds. with receptor affinities comparable to that of 17b-estradiol itself; the 16b-epimers and the estrone
derivs. are bound less well. Thus,
provided that they can be labeled with suitable g-emitting radioisotopes at
sufficiently high specific activity, it appears that the A-ring fluoroestrogens
and 16a-bromo- and 16a-iodo-17b estradiol are excellent
candidates for receptor-based imaging of human breast tumors.