Refine
Has Fulltext
- yes (2)
Is part of the Bibliography
- yes (2)
Document Type
- Journal article (2)
Language
- English (2)
Keywords
- C-X-C motif chemokine receptor 4 (1)
- CXCR4 (1)
- CYP11B enzymes (1)
- PET (1)
- [177Lu]/[90Y]PentixaTher (1)
- [68Ga]PentixaFor (1)
- adrenal incidentaloma (1)
- adrenocortical carcinoma (1)
- endoradiotherapy (1)
- theranostics (1)
Purpose
Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers.
Methods
Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [\(^{123}\)I]IMTO and the most promising compound (R)-1-[1-(4-[\(^{123/}\)I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([\(^{123}\)I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [\(^{131}\)I]IMAZA in one of these patients was performed.
Results
We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [\(^{131}\)I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy.
Conclusion
We developed the new radiopharmaceutical [\(^{123/131}\)I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.
Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.