Breeman W A, Hofland L J, de Jong M, Bernard B F, Srinivasan A, Kwekkeboom D J, Visser T J, Krenning E P
Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands.
Int J Cancer. 1999 May 17;81(4):658-65. doi: 10.1002/(sici)1097-0215(19990517)81:4<658::aid-ijc24>3.0.co;2-p.
The 14-aminoacid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide receptor which is expressed by a variety of tumours. Thus, radiometal-labelled DTPA-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of BN receptor-expressing tumours. A number of such DTPA-BN analogues, [DTPA-D-Tyr6]BN(6-13)NHEt (Et=ethyl), [DTPA-Tyr5,D-Phe6]BN(5-13)NHEt, [DTPA-D-Phe6,Leu13psiPhe14]BN(6-14), [DTPA-Tyr5,D-Phe6,Leu13psiPhe14]BN(5-14), [DTPA-Pro1,Tyr4]BN and [DTPA-Pro1,Tyr4,Nle14]BN, were synthesized and studied for their binding characteristics to the BN receptor on 7315b rat pituitary tumour cell membranes in competition with [125I-Tyr4]BN. The effects of the BN analogues were determined on basal and BN-stimulated prolactin secretion by 7315b cells to distinguish between their agonistic and antagonistic characteristics. Internalization of selected (111)In-labelled BN analogues was studied using the BN receptor-positive 7315b pituitary tumour and the CA20948 and AR42J exocrine pancreas tumour cell lines. The tissue distribution of these (111)In-labelled BN analogues was investigated in 7315b tumour-bearing rats. Two DTPA-conjugated analogues, the antagonist [DTPA-Tyr5,D-Phe6]BN(5-13)NHEt and the agonist [DTPA-Pro1,Tyr4]BN showed the highest affinity for the BN receptor on 7315b cell membranes. Despite similar affinity for the BN receptor, the (111)In-labelled agonist, but not the antagonist, was internalized by the BN receptor-positive tumour cells. Consonant with this observation, the agonist [(111)In-DTPA-Pro1,Tyr4]BN showed much higher specific uptake in BN receptor-positive tissues and tumour than the antagonist [(111)In-DTPA-Tyr5,D-Phe6]BN(5-13)NHEt, with concordant target to background ratios. We conclude that [(111)In-DTPA-Pro1,Tyr4]BN has promising characteristics for applications in nuclear medicine.
14个氨基酸的蛙皮素（BN）对胃泌素释放肽受体具有高亲和力，该受体在多种肿瘤中表达。因此，放射性金属标记的DTPA - BN衍生物是用于表达BN受体肿瘤的受体靶向闪烁扫描和放射治疗的潜在有用放射性配体。合成了许多此类DTPA - BN类似物，[DTPA - D - Tyr6]BN(6 - 13)NHEt（Et = 乙基）、[DTPA - Tyr5,D - Phe6]BN(5 - 13)NHEt、[DTPA - D - Phe6,Leu13psiPhe14]BN(6 - 14)、[DTPA - Tyr5,D - Phe6,Leu13psiPhe14]BN(5 - 14)、[DTPA - Pro1,Tyr4]BN和[DTPA - Pro1,Tyr4,Nle14]BN，并研究了它们与[125I - Tyr4]BN竞争结合7315b大鼠垂体肿瘤细胞膜上BN受体的特性。通过7315b细胞测定BN类似物对基础和BN刺激的催乳素分泌的影响，以区分它们的激动和拮抗特性。使用BN受体阳性的7315b垂体肿瘤以及CA20948和AR42J外分泌胰腺肿瘤细胞系研究了选定的（111）In标记的BN类似物的内化情况。在荷7315b肿瘤大鼠中研究了这些（111）In标记的BN类似物的组织分布。两种DTPA缀合类似物，拮抗剂[DTPA - Tyr5,D - Phe6]BN(5 - 13)NHEt和激动剂[DTPA - Pro1,Tyr4]BN对7315b细胞膜上的BN受体显示出最高亲和力。尽管对BN受体具有相似的亲和力，但（111）In标记的激动剂而非拮抗剂被BN受体阳性肿瘤细胞内化。与该观察结果一致，激动剂[（111）In - DTPA - Pro1,Tyr4]BN在BN受体阳性组织和肿瘤中的特异性摄取比拮抗剂[（111）In - DTPA - Tyr5,D - Phe6]BN(5 - 13)NHEt高得多，靶本底比一致。我们得出结论，[（111）In - DTPA - Pro,1Tyr4]BN在核医学应用中具有良好的特性。
