Biomedical Engineering Reference
In-Depth Information
O
H
O
D-Phe
1
Cys
2
Phe
3
H
H
D-Trp
4
S
S
O
HN
=
S
S
O
Octreotide
Lys
5
H
O
O
NH
N
HO
Thr
8
Cys
7
Thr
6
N
HO
H
NH
2
O
O
OH
HO
O
H
O
H
N
O
O
H
H
Pentetreotide
(SPECT)
O
HN
N
N
O
-
S
S
O
III
In
H
O
O
NH
N
O
-
O
-
N
N
N
HO
H
NH
2
O
O
O
O
OH
HO
-
O
3
S
SO
-
O
N
N
O
H
H
Cy5.5-octreotide
(Fluorescence)
O
HN
O
S
S
H
O
O
NH
N
N
N
HO
H
NH
2
O
O
-
O
3
S
OH
HO
SO
-
FIGURE 7.4
Structure of octreotide and related imaging ligands for measuring the distribution of
SSTRs. Octreotide is a somatostatin analogue that is stabilized against degradation by peptidases through
cyclization (disuli de bridge). Structure-activity relationship revealed that the amino acids phenylalanine-
tryptophane-lysine-threonine (Phe-Trp-Lys-Thr) are essential for the interaction with the somatostatin
receptor 2 (SSTR2). This pharmacophor (shaded area) must be retained when designing a targeted imaging
ligand. The SPECT ligand pentetreotide comprises a chelated indium-111 reporter group (g-photon emitter
radionuclide) while for the optical probe the l uorescent indocyanine dye Cy5.5 has been used. Both reporter
groups are linked to the terminal d-phenylalanine, distant from the pharmacophor group.
can easily be reached also by macromolecular probes. VEGF-R expression has been demonstrated
using radiolabeled probes that are based on the endogenous ligand VEGF or on VEGF-R targeting
antibodies.
The demonstration of altered expression levels of a potential drug target in a pathological condi-
tion is an important, yet not sufi cient, step in the target-validation process.
7.3.2 D3/D4: L
EAD
O
PTIMIZATION
AND
D
RUG
P
ROFILING
By far, most imaging studies in DDD have been carried out in the lead optimization phase. Imaging
has been used for phenotyping disease models and to assess the efi cacy of drug candidates using
structural, functional, metabolic, and more recently also molecular readouts. We will discuss one
