Structure-activity relationships in carboxamide derivatives based on the targeted delivery of radionuclides and boron atoms by means of peripheral benzodiazepine receptor ligands

Article abstract of DOI:10.1021/jm034068b

The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.

Full text of DOI:10.1021/jm034068b

3568
J . Med. Chem. 2003, 46, 3568-3571
Ch a r t 1
Str u ctu r e-Activity Rela tion sh ip s in
Ca r boxa m id e Der iva tives Ba sed on th e
Ta r geted Deliver y of Ra d ion u clid es a n d
Bor on Atom s by Mea n s of P er ip h er a l
Ben zod ia zep in e Recep tor Liga n d s
Andrea Cappelli,*,‡ Gal.la Pericot Mohr,‡
Andrea Gallelli,‡ Germano Giuliani,‡
Maurizio Anzini,‡ Salvatore Vomero,‡
Massimo Fresta,| Patrizia Porcu,†
Elisabetta Maciocco,† Alessandra Concas,†
Giovanni Biggio,† and Alessandro Donati§
Dipartimento Farmaco Chimico Tecnologico, Universita`
degli Studi di Siena, Via A. Moro, 53100 Siena, Italy,
Dipartimento di Scienze Farmacobiologiche, Universita`
“Magna Græcia” di Catanzaro, Complesso “Nin`ı Barbieri”,
88021 Roccelletta di Borgia, Catanzaro, Italy, Dipartimento
di Biologia Sperimentale “B. Loddo”, Universita` degli Studi
di Cagliari, Cittadella Universitaria, SS 554 (km 4.500),
09042 Monserrato (Cagliari), Italy, and Dipartimento di
Scienze e Tecnologie Chimiche e dei Biosistemi, Universita`
degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
infarction, and abnormalities of calcium channels in
heart diseases by positron emission tomography (PET).3
Moreover, compound 1 was conjugated with the anti-
neoplastic drug gemcitabine to selectively increase the
anticancer drug delivery to the tumor cells.4 In this
interesting drug-targeting approach both the selective
interaction of 1 with PBR and the overexpression of this
receptor in the tumor cells were used to increase the
uptake of the antitumoral agent on the part of the
tumoral cells.
Our research in the field led to the design and
synthesis of potent ligands in the class of PK11195
derivatives.5 Moreover, the results of a synthetic-
computational approach based on conformationally
constrained ligands afforded the development of theo-
retical models for the interaction of PBR with the best
known ligands.6 Again, the quinoline carboxamide
derivatives 2a -c (2a : X ) H, R1 ) CH(CH3)CH2CH3,
R2 ) CH3; 2b: X ) F, R1 ) CH(CH3)CH2CH3, R2 ) CH3;
2c: X ) H, R1 ) CH2C6H5, R2 ) CH3) were [11C]-labeled,
and the biodistribution studies suggested that these
compounds are promising PET tracers for the in vivo
imaging of PBR.7 A preliminary evaluation of [11C]-
labeled 2a -c in an excitotoxic model of Huntington’s
disease in rats indicated that benzyl derivative 2c is
an interesting candidate for the in vivo PET monitoring
of neurodegenerative processes.8
Received March 24, 2003
Abstr a ct: The structure-activity relationship studies on
2-quinolinecarboxamide peripheral benzodiazepine receptor
(PBR) ligands have been refined with the aim of using these
ligands as carriers of radionuclides and boron atoms. Some
new ligands show enhanced affinity and steroidogenic activity
with respect to reference compound 1 and are interesting
candidates for radiolabeling and PET studies. Moreover,
carborane derivative 3q, representing the first example of PBR
ligand bearing a carborane cage, can be useful to explore an
alternative mechanism in BNCT.
In tr od u ction . The peripheral benzodiazepine recep-
tor (PBR) was found to be overexpressed in a variety of
tumors (e.g., certain brain tumors, ovarian cancer, liver
tumors, breast carcinoma, colorectal cancer, etc.), and
the PBR expression appears to be related to the tumor
malignancy degree.1 Furthermore, increased concentra-
tions of PBR were observed in lesioned brain areas in a
variety of neuropathologies such as multiple sclerosis,
Alzheimer’s disease, and Huntington’s disease.2
The isoquinolinecarboxamide PK11195 (1, Chart 1)
was the first non-benzodiazepine ligand which was
found both to bind the PBR with nanomolar affinity and
to facilitate the transport of cholesterol from the outer
to the inner mitochondrial membrane, increasing the
rate of pregnenolone synthesis. Compound 1 is nowa-
days the most widely used pharmacological tool for the
study of the expression and the function of PBR (e.g.,
steroidogenesis and apoptosis). For example, compound
1 labeled with positron emitter carbon-11 was used in
the imaging of brain tumors, multiple sclerosis, cerebral
These results stimulated the extension of the struc-
ture-affinity relationship studies to compounds 3 with
the aim of optimizing the interaction of the quinolin-
ecarboxamide derivatives with PBR and once again
developing better candidates for PET studies. Further-
more, the benzylic substituent of compound 2c was
replaced with
a 1,2-dicarba-closo-dodecaboran-1-yl-
methyl moiety in order to obtain a PBR ligand liable to
be labeled with different radionuclides and potentially
useful in boron neutron capture therapy (BNCT).9 By
means of this drug-targeting approach, we expected to
obtain a BNCT agent which accumulated in the tumor
cells and, when radiolabeled, could reveal the tumor
area (e.g., by means of PET) to be subjected to thermal
neutron irradiation. Moreover, the carborane cage could
be used as a small organometallic ligand for radio-
nuclides useful in diagnostic imaging and radiotherapy.
In the present paper we describe the synthesis and
the preliminary pharmacological characterization of new
* To whom correspondence should be addressed. E-mail: cappelli@
unisi.it.
‡ Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi
di Siena.
| Universita` “Magna Græcia” di Catanzaro.
† Universita` degli Studi di Cagliari.
§ Dipartimento di Scienze e Tecnologie Chimiche e dei Biosistemi,
Universita` degli Studi di Siena.
10.1021/jm034068b CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/18/2003

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3569
Sch em e 1a,b
ligand showing a carborane cage in its structure. The
result could have intriguing aspects because PBR is
localized mainly on the outer mitochondrial membrane,
and it has been suggested that mitochondrial events
play a fundamental role in the control of cell death.11
Thus, the irradiation with thermal neutrons could
produce severe damages to the mitochondria bearing
compound 3q bound to PBR. This could lead to cyto-
chrome c release in the cytosol with the formation of a
complex with Apaf-1 and the activation of caspase
cascades up to apoptosis. Therefore, carborane deriva-
tive 3q constitutes an interesting tool to explore an
alternative mechanism in BNCT. Finally, the carborane
moiety of 3q can be used as an organometallic ligand
for radionuclides useful in diagnostic imaging (e.g., Tc-
99m) or radiotherapy (e.g., Re-188)12 in order to develop
new diagnostic agents, radiotherapeutics, or agents
which can be used in both diagnosis and BNCT.
a
In icosahedral cage structure, closed circles represent carbon
atoms, and the vertexes represent BH units. bReagents: (a) B10H14
CH3CN, CH3C6H5.
,
PBR ligands 3. Some of the most potent compounds in
inhibiting the specific binding of [3H]CB 3410 at PBR
were tested for their potential stimulant activity of
steroid biosynthesis as a measure of their capability of
reaching the PBR in vivo.
Resu lts a n d Discu ssion . Ch em istr y. The already
known quinolinecarboxamide derivatives 3g and 3h (2c
in the Introduction) were resynthesized following the
procedure previously described,5 while new target car-
boxamide derivatives 3a -f,i-p were prepared by means
of the chemistry already developed (Supporting Infor-
mation).5,6 Finally, 1,2-dicarba-closo-dodecaboran-1-yl-
methyl derivative 3q was obtained by reaction of
propargyl derivative 3p with a bis(acetonitrile)deca-
borane complex in toluene under reflux conditions
(Scheme 1).
Bin d in g Stu d ies. Compounds 3 were tested for their
activity in inhibiting the specific binding of [3H]CB 3410
to rat cortical membrane in comparison with reference
compound 1. The results of the binding studies (Table
1) revealed that all the tertiary amide derivatives
3b,d ,f,h ,j-q show nanomolar affinity for PBR (IC50
values ranging from 0.45 to 73 nM). In particular, the
most potent 3-chloromethyl derivative 3m showed sub-
nanomolar PBR affinity and was 20 times more potent
than reference compound 1, while 2-fluorophenyl de-
rivative 3j showing nanomolar affinity was, however,
significantly more potent than 1. Thus, these two PBR
ligands (3m ,j) represent interesting candidates for
radiolabeling and PET studies.
Str u ctu r e-Affin ity Rela tion sh ip s. The introduc-
tion of substituents in position 3 of the quinoline nucleus
of compound 3d increased the PBR affinity in variable
degree depending on the stereoelectronic properties of
the substituent involved. The introduction of a methyl
group produced an affinity enhancement of about an
order of magnitude (compare 3h with 3d ), while an
affinity increase of about 2 orders of magnitude was
observed when a chloromethyl substituent was involved
(compare 3m with 3d ). The introduction of a hydroxy-
methyl (compound 3l) or differently substituted ami-
nomethyl groups (compounds 3n ,o) had less dramatic
effects on PBR affinity, and the comparison of the
affinities shown by 3d ,h ,l-o suggests that the presence
in 3-position of substituents showing a wide range of
stereoelectronic properties is compatible with a produc-
tive binding to PBR. This represents valuable informa-
tion for the design of new PBR ligands possessing the
desired properties. Other information concerns (a) the
favorable effect of the introduction of a fluorine atom
in position 2 of the pendent phenyl group (compare 3j
vs 3h ), (b) the incomplete bioisosterism of both the 1,2-
dicarba-closo-dodecaboran-1-ylmethyl (3q) and the pro-
pargyl (3p ) moieties with respect to the benzyl one of
compound 3h , (c) the tolerance showed by the receptor
in accommodating the second benzyl group on the amide
The carborane derivative 3q shows a very good
affinity for PBR so that this compound is the first PBR
Ta ble 1. PBR Binding Affinities of Compounds 3a -q
compd
X
Y
R1
R2
R3
IC50 (nM) ( SEMa
3a
3b
3c
3d
3e
3f
3g
3h b
3i
3j
3k
3l
3m
3n
3o
3p
3q
1
H
H
H
H
H
H
H
H
F
CH
CH
N
CH2C6H5
H
CH3
H
CH3
H
CH3
H
H
H
H
H
2700 ( 198
64 ( 5.3
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2CtCH
CH2C(B10H10)CH
11500 ( 629
38 ( 2.6
N
CH
CH
N
N
N
N
N
N
N
N
N
N
N
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2OH
CH2Cl
CH2N(C2H5)2
CH2N(C2H5)-CH2C6H5
CH3
CH3
6600 ( 501
9.8 ( 1.1
10270 ( 920
4.6 ( 0.7
1490 ( 152
2.2 ( 0.8
11 ( 7
CH3
H
F
CH3
CH2C6H5
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
8.7 ( 1.1
0.45 ( 0.2
12 ( 1.5
13 ( 0.9
32 ( 5.2
73 ( 6.1
8.4 ( 0.9
a
Each value is the mean ( SEM of three determinations and represents the concentration given half the maximum inhibition of
[3H]CB 34 (final concentration 1 nM) specific binding to rat cortical membranes. Compound 3h is referred to the introduction as 2c.
b

3570 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17
Letters
F igu r e 2. Effects of compounds 3h ,j,k ,m and 1 on the plasma
concentrations of pregnenolone (A), progesterone (B), allopreg-
nanolone (C), and corticosterone (D). Rats were killed 30 min
after intraperitoneal administration of 25 mg/kg of compounds
3h ,j,k ,m , or 1. Control animals received the same amount of
vehicle. Data are means ( SEM of six rats. *P < 0.05; **P <
0.001 vs vehicle-treated rats.
F igu r e 1. Effects of compounds 3h ,j,k ,m and 1 on the
concentrations of pregnenolone (A), progesterone (B), and
allopregnanolone (C) in rat cerebral cortex. Rats were killed
30 min after intraperitoneal administration of 25 mg/kg of
compounds 3h ,j,k ,m , or 1. Control animals received the same
amount of vehicle. Data are means ( SEM of six rats. *P <
0.05; **P < 0.001 vs vehicle-treated rats.
PBR affinity and was found to be 20-times more potent
than reference compound 1. Moreover, 2-fluorophenyl
derivative 3j showing nanomolar affinity was, however,
significantly more potent than 1. Thus, these two PBR
ligands (3m ,j) represent interesting candidates for
radiolabeling and PET studies. The powerful activity
of 3h ,j,k in stimulating steroid biosynthesis demon-
strated that these quinolinecarboxamide derivatives are
capable of reaching and interacting with the PBR in vivo
and of stimulating the transport of cholesterol both in
the brain and in peripheral tissue mitochondria.
nitrogen (compare 3k vs 3h ), and (d) the slight superi-
ority of the quinoline bicyclic system with respect to
naphthalene (3d vs 3b and 3h vs 3f). The rationaliza-
tion of these data is now under study as an effort aimed
at both the validation of the theoretical receptor model
previously developped6 and the design of new PBR
ligands furnished with the desired properties.
Effects of Com p ou n d s 3j,h ,k ,m on Ster oid ogen -
esis. Intraperitoneal administration of 3h ,j,k ,m and 1
(25 mg/kg) in rats resulted in a marked increase in the
brain concentration of pregnenolone [F(5,29) ) 17.79;
p < 0.0001], progesterone [F(5,29) ) 18.38; p < 0.0001],
and allopregnanolone [F(5,29) ) 6.07; p < 0.001]
measured 30 min after injection (Figure 1). The effects
of compounds 3h ,j,k were more marked than those
produced by reference compound 1. For example, 3j
increased the pregnenolone, progesterone, and allopreg-
nanolone brain concentrations by 340, 295, and 104%,
respectively (as compared with the control), while
compounds 3m and 1 showed relatively lower increases.
Compounds 3h ,j,k ,m also significantly increased the
amounts of the neuroactive steroids pregnenolone
[F(5,29) ) 3.94; p < 0.01], progesterone [F(5,29) ) 19.21;
p < 0.0001], and allopregnanolone [F(5,29) ) 10.72;
p < 0.001] in plasma (Figure 2) showing effects com-
parable with those shown by reference compound 1.
Finally, compounds 3h ,j,k,m and 1 increased the plasma
concentration of corticosterone [F(5,29) ) 12.78; p <
0.0001], the major adrenal corticosteroid in rat, with 3j
being the most effective (Figure 2).
Furthermore,
1,2-dicarba-closo-dodecaboran-1-yl-
methyl derivative 3q represents the first example of
PBR ligand bearing a carborane cage potentially useful
in BNCT and as an organometallic ligand for radio-
nuclides useful in diagnostic imaging (e.g., Tc-99m) or
radiotherapy (e.g., Re-188).12 Intriguingly, the targeting
of a boron-rich moiety to the mitochondrial receptor of
tumoral cells could represent a new approach to the
anticancer therapy, which could benefit from the key
role of mitochondrial signaling in apoptosis.
Ack n ow led gm en t. The authors are grateful to Prof.
Stefania D’Agata D’Ottavi for the careful reading of the
manuscript. This work was financially supported by
Italian MIUR.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis and the characterization of compounds
3 (chemistry, NMR, MS). This material is available free of
charge via Internet at http://pubs.acs.org.
These results demonstrated that quinolinecarbox-
amide derivatives 3h ,j,k ,m are capable of reaching and
interacting with the PBR in vivo and of stimulating the
cholesterol transport into the mitochondria both in the
brain and in peripheral tissues.
Con clu sion s. The structure-activity relationship
studies on 2-quinolinecarboxamide PBR ligands have
been refined with the aim of using these ligands as
carriers of radionuclides and boron atoms. Among the
newly synthesized compounds, the tertiary amide bear-
ing a chloromethyl group 3m showed subnanomolar
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