| Title |
Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT
|
|---|---|
| Published in |
European Journal of Nuclear Medicine and Molecular Imaging, December 2015
|
| DOI | 10.1007/s00259-015-3232-1 |
| Pubmed ID | |
| Authors |
Theodosia Maina, Hendrik Bergsma, Harshad R. Kulkarni, Dirk Mueller, David Charalambidis, Eric P. Krenning, Berthold A. Nock, Marion de Jong, Richard P. Baum |
| Abstract |
Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4'-DPhe(6),Leu-NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga. Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi. SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi - 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3. [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer. |
X Demographics
The data shown below were collected from the profiles of 4 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 4 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 75% |
| Practitioners (doctors, other healthcare professionals) | 1 | 25% |
Mendeley readers
The data shown below were compiled from readership statistics for 52 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 52 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 14 | 27% |
| Student > Ph. D. Student | 9 | 17% |
| Researcher | 5 | 10% |
| Student > Bachelor | 3 | 6% |
| Other | 2 | 4% |
| Other | 3 | 6% |
| Unknown | 16 | 31% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 11 | 21% |
| Pharmacology, Toxicology and Pharmaceutical Science | 6 | 12% |
| Chemistry | 5 | 10% |
| Biochemistry, Genetics and Molecular Biology | 3 | 6% |
| Agricultural and Biological Sciences | 2 | 4% |
| Other | 6 | 12% |
| Unknown | 19 | 37% |
Attention Score in Context
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 25 March 2021.
All research outputs
#5,957,747
of 23,806,312 outputs
Outputs from European Journal of Nuclear Medicine and Molecular Imaging
#756
of 3,083 outputs
Outputs of similar age
#89,604
of 391,667 outputs
Outputs of similar age from European Journal of Nuclear Medicine and Molecular Imaging
#12
of 56 outputs
Altmetric has tracked 23,806,312 research outputs across all sources so far. This one has received more attention than most of these and is in the 74th percentile.
So far Altmetric has tracked 3,083 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.1. This one has done well, scoring higher than 75% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 391,667 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 76% of its contemporaries.
We're also able to compare this research output to 56 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 78% of its contemporaries.