New alkylating bombesin receptor antagonists

Castiglione, Roberto; Corradi, F.; Gozzini, Luigia; Galantino, Mauro; Lucietto, P.; Molinari, Isabella; Ciomei, Marina

doi:10.1007/978-94-011-3034-9_298

Cited by 2 publications

(4 citation statements)

References 2 publications

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“…Soon thereafter, a shift of paradigm to GRPR-antagonists occurred [3,20] with a wide range of radiolabeled GRPR-antagonists (or GRPR-radioantagonists from now on) being developed and tested via systematic preclinical structure-activity relationships studies (SARs). This transition in nuclear medicine was facilitated by numerous existing GRPRantagonist motifs, developed in previous years either as "cold" (non-radioactive) anticancer drugs, or as molecular tools for elucidating the pharmacology of the bombesin receptor family [3,[21][22][23][24]. As a rule, GRPR-antagonists were generated by structural interventions on the C-terminal BBN(6/7-14) fragment, and in particular on the end Leu-Met-NH 2dipeptide [3,21].…”

Section: Introductionmentioning

confidence: 99%

“…This transition in nuclear medicine was facilitated by numerous existing GRPRantagonist motifs, developed in previous years either as "cold" (non-radioactive) anticancer drugs, or as molecular tools for elucidating the pharmacology of the bombesin receptor family [3,[21][22][23][24]. As a rule, GRPR-antagonists were generated by structural interventions on the C-terminal BBN(6/7-14) fragment, and in particular on the end Leu-Met-NH 2dipeptide [3,21]. As expected, GRPR-antagonists turned out to be safer for human use in view of their inability to activate the GRPR.…”

Section: Introductionmentioning

confidence: 99%

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[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Nock

Kaloudi

Kanellopoulos

et al. 2021

Cancers

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Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DGA-DPhe6,Sar11,LeuNHEt13]BBN(6-13); N4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 ± 0.03 nM) and [99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Nock

Kaloudi

Kanellopoulos

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…Assim, apresentam um largo espectro de atividades biológicas e farmacológicas, podendo atuar na termo e glicorregulação (7), na regulação do comportamento (8), e na regulação de secreções endócrinas e exócrinas (9,10). Além disso, em alguns modelos de culturas de células, esses peptídeos bombesina-similes parecem funcionar como fatores de crescimento autócrinos (11). Vários estudos estão sendo feitos a fim de testar se o uso de antagonistas destes peptídeos poderia ter aplicação clínica no tratamento de tumores como o carcinoma pulmonar de células pequenas (11).…”

Section: Bombesina E Seus Análogos Em Mamíferosunclassified

“…Além disso, em alguns modelos de culturas de células, esses peptídeos bombesina-similes parecem funcionar como fatores de crescimento autócrinos (11). Vários estudos estão sendo feitos a fim de testar se o uso de antagonistas destes peptídeos poderia ter aplicação clínica no tratamento de tumores como o carcinoma pulmonar de células pequenas (11).…”

Section: Bombesina E Seus Análogos Em Mamíferosunclassified

Peptídeos bombesina-símiles: novos reguladores da secreção adeno-hipofisária

Ortiga-Carvalho

Pazos‐Moura

2000

Arq Bras Endocrinol Metab

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A neuromedina B (NB) e o peptídeo liberador de gastrina são peptídeos bombesina-símiles encontrados em mamíferos, inclusive em seres humanos. Ambos inibem a secreção hipofisária de tireotrofina (TSH); entretanto, somente a NB tem importância fisiológica demonstrada. A NB é produzida em abundância em tireotrofos e parece inibir a secreção de TSH por via autócrina, uma vez que o bloqueio do peptídeo endógeno causa aumento na liberação do TSH, tanto in vivo quanto in vitro. A NB é positivamente regulada pelos hormônios tireóideos (HT). Os HT aumentam o conteúdo de neuromedina B e do seu RNAm em adeno-hipófises de ratos hipotireóideos, poucas horas após sua administração, o que coincide com diminuição do TSH sérico. Isto nos levou a sugerir que a NB possa ser um intermediário protéico envolvido na inibição aguda da liberação de TSH induzida pelos HT. O TRH também altera rapidamente a expressão da NB. Quinze e 30 minutos após a administração do TRH em ratos normais já há diminuição do conteúdo hipofisário de NB e dos níveis do seu RNAm. No jejum e diabetes experimental, que se caracterizam por diminuição de HT séricos com níveis inadequadamente normais ou diminuídos de TSH, ocorre aumento do conteúdo de NB e de seu RNAm. O análogo de somatostatina, octreotide, também é capaz de aumentar o conteúdo de NB. Assim, a neuromedina B é um importante inibidor local da secreção de TSH, podendo ser uma via final comum de hormônios e neuro-hormônios que determinam variações na secreção de TSH. ABSTRACTNeuromedin B (NB) and gastrin-releasing peptide (GRP) are mammalian bombesin-like peptides. Both peptides have inhibitory effects on thyrotropin (TSH) secretion, however NB is the one that proved to be physiologically relevant. The administration of NB reduces serum TSH of eu-and hypothyroid rats, while the antiserum against NB, that blocks the endogenous peptide, increases TSH secretion. NB is abundantly produced in thyrotrophs and acts locally as a autocrine factor to inhibit TSH release since isolated pituitaries increase the release of TSH in the presence of the specific antiserum. Thyroid hormones (TH) up-regulate pituitary NB peptide and mRNA content. This is a rapid effect: in hypothyroid rats it is seen within a few hours after a single injection of TH, and coincides with TSH suppression. These results suggest that NB could be an intermediary factor in the acute suppressive effect of TH on TSH secretion. TRH also rapidly changes NB expression. In normal rats, 15 to 30 minutes after TRH administration the pituitary NB peptide and mRNA content are already decreased. In experimental fasting and diabetes mellitus, which are characterized by inappropriately normal or decreased serum TSH, both the NB peptide and its mRNA pituitary content are increased. Octreotide, a somatostatin analog, also is able to increase pituitary neu-

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New alkylating bombesin receptor antagonists

Cited by 2 publications

References 2 publications

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Peptídeos bombesina-símiles: novos reguladores da secreção adeno-hipofisária

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