Background
Methods
Peptide synthesis
General conditions
DOTATATE and HA-DOTATATE
Synthesis of natGa, natLu, and natY reference compounds
Radiolabeling
68Ga labeling
177Lu labeling
Radioiodination of (Leu8,D-Trp22,Tyr25)-somatostatin-28 and Tyr3-octreotide
Determination of lipophilicity
In vitro studies
Determination of IC50 using cell membranes
Dual-tracer internalization studies using AR42J cells
Biodistribution experiments
AR42J tumor model
Biodistribution studies
Results and discussion
Radiolabeling
Lipophilicity
Peptide
|
log
P
O/PBS
|
---|---|
[68Ga]DOTATATE | −3.69 |
[177Lu]DOTATATE | −3.16 |
[68Ga]HA-DOTATATE | −3.12 |
[177Lu]HA-DOTATATE | −2.69 |
In vitro studies
IC50 studies using membrane preparations (sst1–5)
Peptide
|
hsst
1
|
hsst
2
|
hsst
3
|
hsst
4
|
hsst
5
|
---|---|---|---|---|---|
natGa-DOTATATE | >1,000 (2) | 1.2 ± 0.6 (5) | >1,000 (2) | >1,000 (3) | >1,000 (3) |
natLu-DOTATATE | >1,000 (2) | 2.0 ± 0.8 (5) | 162 ± 16 (2) | >1,000 (3) | >1,000 (3) |
natGa-HA-DOTATATE | >1,000 (2) | 1.4 ± 0.8 (5) | >1,000 (2) | >1,000 (3) | 102 ± 65 (4) |
natLu-HA-DOTATATE | >1,000 (2) | 2.0 ± 1.6 (5) | 93 ± 1 (2) | >1,000 (3) | 222 ± 148 (4) |
natY-HA-DOTATATE | n.d. | 2.4 ± 0.3 (2) | n.d. | n.d. | 680 (1) |
Dual-tracer internalization studies
Biodistribution studies
[
68
Ga]DOTATATE
|
[
68
Ga]HA-DOTATATE
| |||
---|---|---|---|---|
Control
|
Competition
|
Control
|
Competition
| |
Blood | 0.3 ± 0.06 | 0.4 ± 0.2 | 0.7 ± 0.3 | 2.5 ± 0.6 |
Heart | 0.3 ± 0.04 | 0.2 ± 0.1 | 0.5 ± 0.2 | 1.0 ± 0.2 |
Lung | 8.4 ± 1.4 | 0.6 ± 0.2 | 13.2 ± 1.0 | 2.5 ± 0.4 |
Liver | 0.5 ± 0.1 | 0.2 ± 0.05 | 1.0 ± 0.2 | 1.0 ± 0.3 |
Intestine | 2.7 ± 0.8 | 0.6 ± 0.2 | 4.0 ± 0.7 | 0.8 ± 0.04 |
Kidney | 3.9 ± 0.5 | 4.1 ± 0.9 | 5.3 ± 1.0 | 17.1 ± 8.7 |
Spleen | 0.9 ± 0.1 | 0.2 ± 0.03 | 1.9 ± 0.8 | 0.7 ± 0.2 |
Muscle | 0.3 ± 0.2 | 0.2 ± 0.1 | 0.2 ± 0.1 | 0.6 ± 0.4 |
Stomach | 15.9 ± 3.9 | 0.7 ± 0.1 | 21.7 ± 4.5 | 1.9 ± 0.8 |
Adrenals | 5.1 ± 1.4 | 0.4 ± 0.1 | 10.8 ± 3.2 | 1.0 ± 0.3 |
Pancreas | 26.1 ± 4.9 | 0.6 ± 0.03 | 36.6 ± 4.3 | 1.5 ± 0.5 |
AR42J tumor | 24.1 ± 4.9 | 2.0 ± 0.1 | 33.6 ± 10.9 | 5.6 ± 0.7 |